Diabetes and Insulin Secretion
http://www.100md.com
《糖尿病学杂志》
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri
CHI, congenital hyperinsulinism; FOXP3, forkhead box P3; GSIS, glucose-stimulated insulin secretion; IPF-1, insulin promoter factor 1; KATP channel, ATP-sensitive K+ channel; PIP2, phosphatidylinositol-4,5-bisphosphate; SUR1, sulfonylurea receptor-1
ABSTRACT
The ATP-sensitive K+ channel (KATP channel) senses metabolic changes in the pancreatic -cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. When KATP channels open, -cells hyperpolarize and insulin secretion is suppressed. The prediction that KATP channel "overactivity" should cause a diabetic state due to undersecretion of insulin has been dramatically borne out by recent genetic studies implicating "activating" mutations in the Kir6.2 subunit of KATP channel as causal in human diabetes. This article summarizes the emerging picture of KATP channel as a major cause of neonatal diabetes and of a polymorphism in KATP channel (E23K) as a type 2 diabetes risk factor. The degree of KATP channel "overactivity" correlates with the severity of the diabetic phenotype. At one end of the spectrum, polymorphisms that result in a modest increase in KATP channel activity represent a risk factor for development of late-onset diabetes. At the other end, severe "activating" mutations underlie syndromic neonatal diabetes, with multiple organ involvement and complete failure of glucose-dependent insulin secretion, reflecting KATP channel "overactivity" in both pancreatic and extrapancreatic tissues.
In the pancreatic -cell, the ATP-sensitive K+ channel (KATP channel) plays an essential role in coupling membrane excitability with glucose-stimulated insulin secretion (GSIS) (1). An increase in glucose metabolism leads to elevated intracellular [ATP]/[ADP] ratio, closure of KATP channels, and membrane depolarization. Consequent activation of voltage-dependent Ca2+ channels causes a rise in [Ca2+]i, which stimulates insulin release (Fig. 1). Conversely, a decrease in the metabolic signal is predicted to open KATP channels and suppress the electrical trigger of insulin secretion. Sulfonylurea drugs promote, and diazoxide suppresses, insulin secretion by binding to the regulatory sulfonylurea receptor-1 (SUR1) subunit and inhibiting, or activating, KATP channel current, respectively (2). The electrical pathway is modulated by KATP channeleCindependent mechanisms; nutrient metabolites and incretins affect secretion at various stages downstream of KATP channel (3,4), but the drug effects underscore the central role of KATP channeleCdependent regulation.
Alterations in the metabolic signal, in the sensitivity of KATP channel to metabolites, or in the number of active KATP channels, could each disrupt electrical signaling in the -cell and alter insulin release. In support of this prediction, earlier studies implicated reduced or absent KATP channel activity in the -cell as causal in congenital hyperinsulinism (CHI) in humans (5). CHI is a rare, mostly recessive, disorder characterized by constitutive insulin secretion despite low blood glucose. If left untreated, severe mental retardation and death may result. Mutations in KATP channel that reduce channel expression, decrease stimulation of the channel by MgADP, or abolish channel activity account for a majority of all CHI mutations (6,7,8,9). Conversely, mutations that result in "overactive" channels should decrease membrane excitability and impair glucose sensing by the -cell. In this scenario, insulin secretion will be reduced and a diabetic phenotype is predicted. A clear picture is now emerging from both animal and human studies that such KATP channel mutations can indeed cause diabetes. The first part of this review will detail the rapidly emerging clinical evidence for involvement of KATP channel mutations in neonatal and type 2 diabetes and the cellular basis of the disease. The second part will consider the structure-function relationships of the KATP channel and molecular mechanisms that underlie diabetes in which mutations in KATP are causal.
Part 1: -cell KATP channel and diabetes: the emerging genetic and clinical picture
Mutations in Kir6.2 underlie neonatal diabetes.
Given the above paradigm, any gain of KATP channel function is expected to suppress GSIS. This prediction was originally confirmed by the striking neonatal diabetic phenotype of two different genetic models: 1) mice with targeted disruption of the pancreatic -cell glucokinase gene (10) and 2) transgenic mice expressing -cell KATP channels with decreased sensitivity to inhibitory ATP (i.e., "overactive" KATP channel) (11). In each case, acute neonatal hyperglycemia together with ketoacidosis, leading to death within a few days, was observed. In the latter model (Fig. 2A), blood insulin is at or below the level of detection but insulin is clearly present in the pancreas (11). In each case, overactive KATP channel activity, with a failure to switch on insulin secretion, is the logical underlying mechanism; this is due to altered metabolic signal in the former (12) and insensitivity to the normal metabolic signal in the latter (11).
The obvious prediction of these mouse models is that genetically induced ATP insensitivity of -cell KATP channels could underlie impaired insulin release and neonatal diabetes in humans (13,14). Rare in occurrence (1:400,000 births), neonatal diabetes is usually diagnosed within the first 3 months of life and relies on insulin administration to treat the hyperglycemia (15). In transient neonatal diabetes, which is milder, hyperglycemia usually resolves within 18 months, whereas the permanent form requires insulin treatment for life. Until recently, the cause of the majority of permanent neonatal diabetes cases has remained unknown. Homozygous and compound heterozygous mutations in glucokinase, the rate-limiting enzyme of glucose metabolism in islet cells, cause isolated permanent neonatal diabetes and account for a minority of cases (at least six families reported to date) (16,17). Similarly, compound heterozygous or homozygous mutations in insulin promoter factor 1 (IPF-1), an essential transcriptional regulator of pancreatic development, underlie a fewer number of cases (18,19). Other rare forms of permanent neonatal diabetes are associated with multiple deficiencies. These include Wolcott-Rallison syndrome, characterized by infancy-onset diabetes along with growth and mental retardation and caused by mutations in EIF2AK3, a regulator of protein synthesis (20,21). In addition, defects of forkhead box P3 (FOXP3) underlie IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, which also includes neonatal-onset diabetes (22). While defects in glucokinase and KATP channel are predicted to impair glucose sensing of the -cell, leading to suppressed insulin release, mutations in IPF-1 and FOXP3 underlie decreased -cell mass; IPF-1 through impaired pancreatic development and FOXP3 through autoimmune destruction of pancreatic islets (23,24). In contrast to permanent neonatal diabetes, a majority of transient neonatal diabetes cases are attributable to paternal imprinting at chromosome 6q24 (25). Two candidate genes have been identified: ZAC (zinc finger protein that regulates apoptosis and cell-cycle arrest) and HYAMI (hydatidiform mole-associated and imprinted transcript), an untranslated mRNA of unknown function.
Recent genetic studies demonstrate that heterozygous mutations in KCNJ11, encoding the Kir6.2 subunit of the KATP channel, underlie neonatal diabetes in humans, accounting for both permanent neonatal diabetes (26eC31), in which type 1 autoantibodies are absent, and relapsing transient neonatal diabetes, in which chromosome 6 abnormalities were excluded (32,33). Both de novo appearance of Kir6.2 mutations and familial transmission have been reported (26eC31). Significantly, in all examined families, neonatal diabetes was observed only in individuals carrying the Kir6.2 mutations and not in other family members. Interestingly, in a subgroup of patients carrying Kir6.2 mutations, permanent neonatal diabetes is part of a larger syndrome that often includes marked developmental delay in motor intellectual and social skills, muscle weakness, dysmorphic features, and epilepsy (27,29,30). Despite normal-sized cortex and cerebellum, a majority of patients with syndromic permanent neonatal diabetes also display language and social development that is delayed from 5 to 48 months (27). There appears to be no correlation between the age of diagnosis and the severity of the permanent neonatal diabetes (syndromic versus nonsyndromic). As Kir6.2 represents the pore-forming subunit of KATP channels in skeletal muscle and in neurons throughout the brain (34,35), differentially overactive KATP channels in extrapancreatic tissue can potentially account for neurological disorders associated with this subgroup of patients through as-yet-to-be-defined mechanisms.
Neonatal diabetic subjects with Kir6.2 mutations demonstrate varying levels of C-peptide (27,31eC33,36) consistent with a varying degree of -cell dysfunction and likely accounting for the variable hyperglycemia often observed with neonatal diabetes. Consistent with a defect at the level of KATP channel, affected patients carrying R201 mutations did not secrete insulin in response to glucose or glucagon but did in response to sulfonylurea (tolbutamide), albeit at subnormal levels (Fig. 2B) (27,30). Importantly, several patients have now been weaned from insulin onto glibenclamide therapy, and at 1- to 6-month follow-ups, blood glucose has been well controlled without insulin supplement (31,36). In many cases, however, the oral dosage of sulfonylureas significantly exceeds (by several-fold) the doses commonly used to treat type 2 diabetes (36,37). Consistent with this clinical observation, the neonatal diabeteseCcausing mutations in Kir6.2 are frequently associated with a concomitant decrease in sensitivity of the KATP channel to sulfonylureas (27,38,39), which may underlie the increased therapeutic dosages.
As additional mutations are uncovered, it is becoming clear that the temporal presentation of the disease can be quite variable. One patient was diagnosed at only 26 weeks of age (27) and another at 5 years (32). Within a single pedigree, one Kir6.2 mutation (C42R) is shown to underlie transient neonatal diabetes, childhood-onset diabetes, as well an apparently type 2 diabetes, all in different carriers (33). Such late presentation suggests that the disease may become apparent at much later ages than typically ascribed, consistent with the notion that the mildest forms of the disease may not manifest until adulthood. This raises the additional possibility that if the disease manifests postnatally, it may be misdiagnosed as type 1 diabetes. So far, however, screening of children diagnosed with type 1 diabetes before 2 years of age, and lacking predisposing HLA genotypes, has failed to demonstrate a significant number of KCNJ11 mutations (28).
Polymorphisms of Kir6.2 predispose to adult-onset diabetes.
Numerous studies have now examined the association of KATP channel polymorphisms with late-onset type 2 diabetes (40eC44). By suppressing excitability, KATP channel polymorphisms that increase channel activity could, in combination with other environmental and genetic factors, contribute to chronically impaired -cell function. In the face of insulin resistance, this is expected to exacerbate the hyperglycemic state. Although results from initial studies are conflicting (45,46), large-scale association studies and meta-analyses have now identified the E23K polymorphism in KCNJ11 as a slight, but significant, risk factor in the complex development of type 2 diabetes (42,44,47eC50). However, given the high allelic frequency of E23K in the general population (frequency of heterozygous EK genotype = 47%; homozygous KK genotype = 12%), the polymorphism is likely to represent a large population-attributable risk (41,48,51,52). Importantly, a recent haplotype analysis of the Kir6.2/SUR1 gene region has demonstrated a strong allelic association of E23K in Kir6.2 with a polymorphism in SUR1 (A1369S), raising the possibility that E23K alone may not entirely account for the reported association with type 2 diabetes (49).
Cellular basis of KATP channel diabetes.
Recombinant expression of mutant channels indicates that both the type 2eCassociated polymorphism (E23K) and neonatal diabeteseCassociated Kir6.2 mutations result in reduced sensitivity to intracellular ATP, either by reducing ATP affinity per se or indirectly via an increase in the intrinsic open-state stability (27,38,39,51,53) (see below). At the cellular level, an important question is: Just how much change in ATP sensitivity is necessary to cause significant impairment of insulin secretion The diabetic phenotype of transgenic mice expressing "overactive" KATP channels in -cells predicted the correlate disease in humans and is a potentially relevant model (11). These mice express Kir6.2 subunits with truncated NH2-termini, which causes a 10-fold reduction of ATP sensitivity in heterologously expressed channels. Transgenic F1 mice from four of five founder lines expressing the truncated channels were severely hyperglycemic, and hypoinsulinemic, and died as neonates by day 5, most likely from acute ketoacidosis (Fig. 2A). Electrophysiology confirmed functional expression of KATP channels with reduced ATP sensitivity, but only approximately fourfold relative to wild type.
Heterologously expressed Kir.2[E23K]-SUR1 channels exhibit even more modest 2- and 1.5-fold reductions in ATP sensitivity for homozygous (Kir6.2[E23K]) and heterozygous (Kir6.2[E23K] + Kir6.2wt) channels, respectively (51 and J.C.K., unpublished observations: K1/2 [ATP] for Kir6.2wt = 10.7 ± 1.9 e蘭ol/l, Kir6.2[E23K] = 17.6 ± 0.9 e蘭ol/l [expressed in COSm6 cells]), as well as enhanced MgADP stimulation (51,52,53,54). E23K is in linkage disequilibrium with another Kir6.2 polymorphism, I337V, which itself has no reported effect on channel activity (51,53). Another study reported no reduction of ATP sensitivity of E23K/I337V channels, but instead showed enhanced stimulatory effects of palmitoyl-CoA on E23K/I337V mutant Kir6.2 channels (55). As discussed below, a small increase in intrinsic open-state stability can underlie a decrease in apparent ATP sensitivity, as well as an increase in sensitivity to activator molecules (51eC54,56). It seems likely that increased palmitoyl-CoA sensitivity in the latter study, as well as increased MgADP sensitivity and reduced ATP sensitivity in the previous study, all reflect just such an increase. In all cases, the net effect will be reduced glucose sensing by the -cell, and, in support, a small effect of the E23K variant on insulin release was observed during intravenous and oral glucose tolerance tests (43,57,58).
E23K also has a strong allelic association with a SUR1 polymorphism (A1369S), raising the possibility that the SUR1 variant may influence, or account for, altered channel activity (49). The effect of the A1369S polymorphism on channel activity is not known (51,55), but the possibility should be acknowledged that alone or in combination with E23K, it contributes to altered ATP sensitivity. (In our unpublished studies of E23K, reconstituted KATP channels carried both the I337V and A1369S polymorphisms.)
What of the ATP sensitivity of different neonatal diabetes mutants Gloyn et al. (27) initially showed an 35-fold loss of ATP sensitivity for homozygous R201H mutant channels, but almost no shift in a 1:1 mixture of wild-type and R201H mutant subunits, expected to recapitulate the heterozygous state of the disease. Assuming a 1:1 expression and random assembly, 16 different subunit arrangements are formally possible, making the analysis of mixed expression very complex (51,53,59,60). However, as acknowledged, 1 of 16 of the expressed channels are expected to be pure mutant, and this alone could give rise to significant currents at physiological [ATP]/[ADP] ratios. Other mutations (Q52R, I296L I182V, V59G, V59M, Y330C, and F333I) have now been analyzed, demonstrating shifts in ATP sensitivity of up to 1,000-fold for homozygous V59G and I296L mutant channels (38,39). Again, much lesser shifts were observed in heterozygous expression, but, without analyzing each subunit combination separately, it remains speculative as to exactly what channel activity can be expected in vivo.
Nonelectrical consequences of altered KATP channel activity.
At this juncture, we cannot preclude nonelectrical secondary mechanisms underlying KATP channeleCinduced diabetes. Mice with overactive -cell KATP channels are profoundly diabetic within a few days of birth (11). Morphologically, the size, distribution, and architecture of the islets are unperturbed at the earliest stages of diabetes (days 1eC3), but collapse of islet architecture, with diffuse distribution of the - and -cells throughout the pancreas, was observed at later stages (after day 3). A similar mechanistic progression may occur in KATP channeleCinduced permanent neonatal diabetes and may underlie some of the reduced sulfonylurea-sensitive insulin release (27). Moreover, a recent transgenic study overexpressing the transient neonatal diabetes locus (6q24) implicated fluctuations in -cell mass and insulin content in the progression of transient neonatal diabetes from the neonatal diabetic phase into remission and ultimately to late-onset diabetes (61). If a similar pathophysiology occurs in transient neonatal diabetes patients carrying Kir6.2 mutations, this would be consistent with secondary, nonelectrical consequences of altered -cell KATP channel activity. Secondary complications do occur in the converse disease progression resulting from reduced KATP channel density. Transgenic mice lacking KATP channels in 70% of -cells, due to -cell expression of dominant-negative Kir6.2 transgene, hypersecrete throughout as adults (14), but mice completely lacking KATP channels are reportedly hyperinsulinemic as neonates and then progress to reduced GSIS and glucose intolerance as adults (62eC64). Importantly, when exposed to a high-fat diet, both Kir6.2eC/eC mice and Kir6.2[AAA] transgenic mice progress rapidly to severely undersecreting diabetes (65). While these hyperexcitable mice, with reduced KATP channel activity, thus have a very different response to those with overactive KATP channels, they do suggest that profound nonelectrical consequences can follow an initial electrical disturbance.
In addition to Kir6.2 defects, loss or reduction of KATP channel activity can also occur due to loss-of-function mutations of the regulatory SUR1 subunit; such mutations are the most frequent cause of CHI (5). Clinical data indicate that CHI patients carrying SUR1 mutations can also progress to glucose intolerance and, in some cases, overt diabetes (66).
Finally, noneC-cell mechanisms must be considered. Kir6.2 is the pore-forming subunit of -cell, muscular, and neuronal KATP channels (34). In skeletal muscle, or in neurons, overactive KATP channel could potentially underlie the muscle weakness reported in syndromic permanent neonatal diabetes (27,29). Glucose uptake by skeletal muscle and adipose may also be dependent on KATP channel activity (67), and overactivity in syndromic permanent neonatal diabetes could compromise this function. In neurons, metabolic sensing is altered with loss of KATP channels (35,68). Again, the unknown consequences of KATP channel overactivity could underlie developmental defects that are also observed in syndromic permanent neonatal diabetes (27,29). Complete understanding of the mechanisms by which Kir6.2 mutations cause neonatal diabetes will require mechanistic molecular analysis of disease-causing mutations (32,33,38,39), generation of transgenic mouse models of neonatal diabetes (11), and analysis of virally infected -cells or insulinoma cell lines expressing altered KATP channel.
Part 2: KATP channeleCdependent diabetes: the molecular defects
The KATP channel: structure and function.
Structurally, the pancreatic KATP channel consists of two unrelated subunits: a sulfonylurea receptor (the SUR1 isoform) that is a member of the ABC transporter family and a potassium channel subunit (Kir6.2) that forms the central ion-conducting pathway (Fig. 3A). The mature KATP channel exists as an octamer of Kir6.2 and SUR1 subunits in a 4:4 stoichiometry (Fig. 3B) (59,69,70). The signature ATP inhibition of the channel results from binding to the pore-forming Kir6.2 subunit (71,72,73,74,75,76). Importantly, the inhibitory concentration of ATP causing half-maximal channel inhibition is in the micromolar range (K1/2[ATP] 10 e蘭ol/l for native KATP channel) (77), yet cytosolic [ATP] is in the millimolar range (1eC5 mmol/l) and changes little in the presence of high glucose (78). This observation implicates MgADP, rather than ATP, as the primary physiological regulator of channel activity. Through interaction with SUR1, MgADP "stimulates" channel activity by countering ATP inhibition (8,79eC83). SUR1 mutations that abolish MgADP action, but do not alter ATP sensitivity, also abolish channel activity in vivo and underlie CHI (8,84). It should be pointed out, however, that despite the essential regulatory role of MgADP, ATP sensitivity of the channel will still be critical in determining the magnitude of KATP channel current. For a given [MgADP], KATP channel mutations that decrease ATP sensitivity will enhance absolute currents in the physiologic range of ATP, and the net effect of enhanced KATP channel current is a decrease in -cell excitability.
Molecular mechanisms of KATP channeleCinduced neonatal diabetes.
Multiple permanent neonatal diabetes mutations have now been identified in Kir6.2 (Fig. 3C). To date, the most frequently mutated residues are R201 and V59; heterozygous mutations of these residues have been detected in multiple probands (27,29,30). Y330C accounted for three cases of permanent neonatal diabetes (28,30), whereas K170 substitutions accounted for two permanent neonatal diabetes cases (K170N and K170R) (29). Q52R, I296L, R50P, F33I, and E322K have all been found in one proband each (28,29,31). Kir6.2 mutations causing transient neonatal diabetes include G53, I182, and C42 (32,33).
These mutations could reduce ATP sensitivity 1) directly by decreasing the affinity of the ATP-binding pocket for the nucleotide, 2) indirectly by an increase in the intrinsic stability of the open state of the channel, or 3) indirectly by an increased sensitivity to the counteractivation by MgADP or by phosphatidylinositol-4,5-bisphosphate (PIP2) or other phospholipids. Consistent with a direct effect on binding, R50, I182, Y330, F333, and R201 have all previously been implicated as putative ATP-binding residues in Kir6.2 (27,74,85). Modeling of the COOH-terminus of Kir6.2, based on homology with the crystal structure of the related Kir3.1, predicts that I182 resides in a hydrophobic pocket that coordinates the adenine ring of ATP (75), while positively charged R201 and R50 are predicted to interact electrostatically with the phosphate tail of ATP (75,85,86). Both Y330 and F333 also predicted to lie close to the phosphate tail in the binding pocket (87).
Fully consistent with the above structural model of the ATP-binding pocket, functional characterization now demonstrates a significant decrease in the ATP sensitivities of these mutants (27,32,38,39). In the case of I182V, R201C, R201H, and F333I, these mutations do not alter gating of the channel and are, therefore, likely to directly alter ATP affinity at the binding pocket. A few additional residues in the NH2- and COOH-terminus are also likely to be involved in ATP binding (71,73,75,76,88,89), and we speculate that substitutions at these residues would also be disease causing.
With respect to indirect channel mechanisms, mutations that alter channel gating in the absence of ATP can have profound effects on apparent ATP sensitivity (73,76,90). Such mutations are found throughout the Kir6.2 subunit. In some cases, these "open-state stability" mutations are located in transmembrane segments, a significant distance from the putative ATP-binding domain (86,91). Many, including E23K, stabilize the open state of the channel, thereby increasing the channel opening independently of ATP and indirectly reducing the apparent affinity for ATP (51,54). The reported loss of ATP sensitivity coupled with high open probability in the Q52R, C42R, Y330C, I1296L, and V59G mutations suggests such a mechanism in these disease mutations (38,39). Consistent with the functional interpretation, Q52 and V59 are located within the predicted slide helix region of Kir6.2 and may regulate channel gating by coupling the ATP-binding site physically to the gating region (75,86). The second transmembrane helices in each of the Kir6.2 subunits converge at the so-called "bundle crossing" and may form the ligand-controlled gate (Fig. 3C) (86,91). An effect on the gate region of the channel might then explain the diabetes-causing effects of mutations at residue K170 (K170N and K170R; Fig. 3) within this region (29).
Since all proteins are evolutionarily tailored to generate specific functions, it follows that disease-causing mutations are most likely to cause loss of the specific function. In the present context, loss of high-affinity inhibition by ATP, either directly or indirectly, is thus the most likely mechanism to underlie the net "gain of function" that underlies neonatal diabetes. However, it is conceivable that spontaneous mutations may also cause an increase in an activating function, such as an increase in the MgADP affinity of SUR1. Alternately, mutations could increase the affinity for PIP2 or other phospholipids, which serve as activators of the channel. In this regard, one or two rare mutations engineered into SUR1 (83,92) increase activation by MgADP, and they could potentially appear spontaneously. Mutations of Kir2.1, a related K channel subunit, underlie Andersen’s syndrome, which is characterized by dysmorphic facial features, epilepsy, and cardiac arrhythmias (93,94). It is argued that these mutations alter Kir2.1 channel function by modulating the phospholipids sensitivity (94). Similarly, many mutations in KATP are likely to affect apparent PIP2 sensitivity by changes in intrinsic open-state stability (54) or by change in affinity. Although none have been reported, it remains possible that neonatal diabetes could also result from gain of function due to an increased affinity for PIP2.
Perspectives and prospects.
The 10-year effort that first yielded the molecular basis of KATP channel activity (77,79) permitted the generation of animal models of channel dysfunction (11) and paved the way to genetic determination of predisposing polymorphisms in type 2 diabetes (41,45,46,95) and disease-causing mutations in both CHI (5) and neonatal diabetes (27,29,33). This in turn has led to an immediate understanding of the likely molecular basis of permanent neonatal diabetes and to improved therapy (31,36). This progression is a dramatic demonstration of the power of multidisciplinary biology in disease analysis. The current results elucidate the molecular basis of a traumatic neonatal disease and exciting possibilities for improvement in treatment options.
KATP channel may be involved in a whole spectrum of diabetes. For the E23K polymorphism, the effect on nucleotide sensitivity is modest, and only in the proper genetic and environmental background may channel overactivity appreciably influence -cell function. Mutations resulting in greater gain of function may still be found to underlie childhood diabetes, while mutations that result in more significant gain of function are likely to give rise to an earlier and more severe form of diabetes, as in permanent neonatal diabetes. In the most severe cases, KATP channel overactivity in extrapancreatic tissue likely contributes to multiorgan syndromic permanent neonatal diabetes. Sulfonylureas may provide dramatic improvement in therapeutic options for neonatal diabetes (27,31,33), but the sulfonylurea-desensitizing effect of open-stateeCstabilizing mutations (39,56,96) and the possibility of secondary nonelectrical consequences heed caution regarding whether this is a panacea.
ACKNOWLEDGMENTS
The authors’ experimental work has been supported by National Institutes of Health Grant DK69445 (to C.G.N.) and Washington University Diabetes Research and Training Center Pilot and Feasibility Award DK20579 (to J.C.K.).
REFERENCES
Ashcroft FM, Rorsman P: ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion. Biochem Soc Trans18 :109 eC111,1990
Aguilar-Bryan L, Bryan J: Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev20 :101 eC135,1999
Aizawa T, Komatsu M, Asanuma N, Sato Y, Sharp GW: Glucose action ‘beyond ionic events’ in the pancreatic beta cell. Trends Pharmacol Sci19 :496 eC499,1998 [erratum in Trends Pharmacol Sci20:124, 1999]
Komatsu M, Sato Y, Aizawa T, Hashizume K: KATP channel-independent glucose action: an elusive pathway in stimulus-secretion coupling of pancreatic beta-cell (Review). Endocr J48 :275 eC288,2001
Huopio H, Shyng SL, Otonkoski T, Nichols CG: K(ATP) channels and insulin secretion disorders (Review). Am J Physiol Endocrinol Metab283 :E207 eCE216,2002
Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J: Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science268 :426 eC429,1995
Nestorowicz A, Glaser B, Wilson BA, Shyng SL, Nichols CG, Stanley CA, Thornton PS, Permutt MA: Genetic heterogeneity in familial hyperinsulinism. Hum Mol Genet7 :1119 eC1128,1998 [erratum in Hum Mol Genet7:1527, 1998]
Nichols CG, Shyng SL, Nestorowicz A, Glaser B, Clement JP 4th, Gonzalez G, Aguilar-Bryan L, Permutt MA, Bryan J: Adenosine diphosphate as an intracellular regulator of insulin secretion. Science272 :1785 eC1787,1996
Cartier EA, Conti LR, Vandenberg CA, Shyng SL: Defective trafficking and function of KATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent hyperinsulinemic hypoglycemia of infancy. Proc Natl Acad Sci U S A98 :2882 eC2887,2001
Terauchi Y, Sakura H, Yasuda K, Iwamoto K, Takahashi N, Ito K, Kasai H, Suzuki H, Ueda O, Kamada N, et al.: Pancreatic beta-cell-specific targeted disruption of glucokinase gene: diabetes mellitus due to defective insulin secretion to glucose. J Biol Chem270 :30253 eC30256,1995
Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CG: Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell100 :645 eC654,2000
Sakura H, Ashcroft SJ, Terauchi Y, Kadowaki T, Ashcroft FM: Glucose modulation of ATP-sensitive K-currents in wild-type, homozygous and heterozygous glucokinase knock-out mice. Diabetologia41 :654 eC659,1998
Ashcroft FM, Rorsman P: Type 2 diabetes mellitus: not quite exciting enough (Review). Hum Mol Genet13 :R21 eCR31,2004
Nichols CG, Koster JC: Diabetes and insulin secretion: whither KATP (Review). Am J Physiol Endocrinol Metab283 :E403 eCE412,2002
Polak M, Shield J: Neonatal and very-early-onset diabetes mellitus. Semin Neonatol9 :59 eC65,2004
Njolstad PR, Sovik O, Cuesta-Munoz A, Bjorkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI: Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med344 :1588 eC1592,2001
Njolstad PR, Sagen JV, Bjorkhaug L, Odili S, Shehadeh N, Bakry D, Sarici SU, Alpay F, Molnes J, Molven A, Sovik O, Matschinsky FM: Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes52 :2854 eC2860,2003
Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF: Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet15 :106 eC110,1997
Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A, Jornayvaz FR, Theintz GE, Michielin O, Melloul D, Philippe J: Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J Clin Endocrinol Metab88 :4398 eC4406,2003
Biason-Lauber A, Lang-Muritano M, Vaccaro T, Schoenle EJ: Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. Diabetes51 :2301 eC2305,2002
Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C: EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet25 :406 eC409,2000
Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD: The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet27 :20 eC21,2001
Roberts J, Searle J: Neonatal diabetes mellitus associated with severe diarrhea, hyperimmunoglobulin E syndrome, and absence of islets of Langerhans. Pediatr Pathol Lab Med15 :477 eC483,1995
Jonsson J, Carlsson L, Edlund T, Edlund H: Insulin-promoter-factor 1 is required for pancreas development in mice. Nature371 :606 eC609,1994
Gardner RJ, Mackay DJ, Mungall AJ, Polychronakos C, Siebert R, Shield JP, Temple IK, Robinson DO: An imprinted locus associated with transient neonatal diabetes mellitus. Hum Mol Genet9 :589 eC596,2000
Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, Costa T, Temple IK, Hattersley AT, Ellard S: Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab89 :3932 eC3935,2004
Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT: Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med350 :1838 eC1849,2004
Edghill EL, Gloyn AL, Gillespie KM, Lambert AP, Raymond NT, Swift PG, Ellard S, Gale EA, Hattersley AT: Activating mutations in the KCNJ11 gene encoding the ATP-sensitivie K+ channel subunit Kir6.2 are rare in clinically defined type 1 diabetes diagnosed before 2 years. Diabetes53 :2998 eC3001,2004
Massa O, Iafusco D, D’Amato E, Gloyn AL, Hattersley AT, Pasquino B, Tonini G, Dammacco F, Zanette G, Meschi F, Porzio O, Bottazzo G, Crino A, Lorini R, Cerutti F, Vanelli M, Barbetti F, the Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetology: KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat25 :22 eC27,2005
Vaxillaire M, Populaire C, Busiah K, Cave H, Gloyn AL, Hattersley AT, Czernichow P, Froguel P, Polak M: Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes53 :2719 eC2722,2004
Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Sovik O, Njolstad PR: Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes53 :2713 eC2718,2004
Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JP, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT: Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet14 :925 eC934,2005
Yorifuji T, Nagashima K, Kurokawa K, Kawai M, Oishi M, Akazawa Y, Hosokawa M, Yamada Y, Inagaki N, Nakahata T: The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J Clin Endocrinol Metab90 :3174 eC3178,2005
Seino S, Iwanaga T, Nagashima K, Miki T: Diverse roles of KATP channels learned from Kir6.2 genetically engineered mice. Diabetes49 :311 eC318,2000
Yamada K, Ji JJ, Yuan H, Miki T, Sato S, Horimoto N, Shimizu T, Seino S, Inagaki N: Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. Science292 :1543 eC1546,2001
Zung A, Glaser B, Nimri R, Zadik Z: Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J Clin Endocrinol Metab89 :5504 eC5507,2004
Codner E, Flanagan S, Ellard S, Garcia H, Hattersley AT: High-dose glibenclamide can replace insulin therapy despite transitory diarrhea in early-onset diabetes caused by a novel R201L Kir6.2 mutation (Letter). Diabetes Care28 :758 eC759,2005
Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM: Molecular basis of Kir6.2 mutations associated with neonatal diabetes plus neurological features. Proc Natl Acad Sci U S A101 :17539 eC17544,2004
Koster JC, Remedi MS, Dao C, Nichols CG: ATP and sulfonylurea sensitivity of mutant ATP-sensitive K+ channels in neonatal diabetes: implications for pharmacogenomic therapy. Diabetes54 :2645 eC2654,2005
Inoue H, Ferrer J, Welling CM, Elbein SC, Hoffman M, Mayorga R, Warren-Perry M, Zhang Y, Millns H, Turner R, Province M, Bryan J, Permutt MA, Aguilar-Bryan L: Sequence variants in the sulfonylurea receptor (SUR) gene are associated with NIDDM in Caucasians. Diabetes45 :825 eC831,1996
Hani EH, Boutin P, Durand E, Inoue H, Permutt MA, Velho G, Froguel P: Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians. Diabetologia41 :1511 eC1515,1998
Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM: Large-scale association studies of variants in genes encoding the pancreatic -cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes52 :568 eC572,2003
’t Hart LM, van Haeften TW, Dekker JM, Bot M, Heine RJ, Maassen JA: Variations in insulin secretion in carriers of the E23K variant in the KIR6.2 subunit of the ATP-sensitive K+ channel in the -cell. Diabetes51 :3135 eC3138,2002
Barroso I, Luan J, Middelberg RP, Harding AH, Franks PW, Jakes RW, Clayton D, Schafer AJ, O’Rahilly S, Wareham NJ: Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biology1 :E20 ,2003
Sakura H, Wat N, Horton V, Millns H, Turner RC, Ashcroft FM: Sequence variations in the human Kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in while Caucasian subjects or evidence of abnormal function when expressed in vitro. Diabetologia39 :1233 eC1236,1996
Inoue H, Ferrer J, Warren-Perry M, Zhang Y, Millns H, Turner RC, Elbein SC, Hampe CL, Suarez BK, Inagaki N, Seino S, Permutt MA: Sequence variants in the pancreatic islet -cell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM. Diabetes46 :502 eC507,1997
Laukkanen O, Pihlajamaki J, Lindstrom J, Eriksson J, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Tuomilehto J, Uusitupa M, Laakso M, the Finnish Diabetes Prevention Study Group: Polymorphisms of the SUR1 (ABCC8) and Kir6.2 (KCNJ11) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. J Clin Endocrinol Metab89 :6286 eC6290,2004
Love-Gregory L, Wasson J, Lin J, Skolnick G, Suarez B, Permutt MA: E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of type II diabetes in Caucasians as the PPARgamma Pro12Ala variant (Letter). Diabetologia46 :136 eC137,2003
Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D: Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes53 :1360 eC1368,2004
Riedel MJ, Steckley DC, Light PE: Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes (Review). Hum Genet116 :133 eC145,2005
Schwanstecher C, Meyer U, Schwanstecher M: KIR6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic -cell ATP-sensitive K+ channels. Diabetes51 :875 eC879,2002
Schwanstecher C, Schwanstecher M: Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2 diabetes. Diabetes51 (Suppl. 3) :S358 eCS362,2002
Schwanstecher C, Neugebauer B, Schulz M, Schwanstecher M: The common single nucleotide polymorphism E23K in KIR6.2 sensitizes pancreatic -cell ATP-sensitive potassium channels toward activation through nucleoside diphosphates. Diabetes51 (Suppl. 3) :S363 eCS367,2002
Enkvetchakul D, Nichols CG: Gating mechanism of KATP channels: function fits form. J Gen Physiol122 :471 eC480,2003
Riedel MJ, Boora P, Steckley D, de Vries G, Light PE: Kir6.2 polymorphisms sensitize -cell ATP-sensitive potassium channels to activation by acyl CoAs: a possible cellular mechanism for increased susceptibility to type 2 diabetes Diabetes52 :2630 eC2635,2003
Koster JC, Sha Q, Nichols CG: Sulfonylurea and K(+)-channel opener sensitivity of K(ATP) channels: functional coupling of Kir6.2 and SUR1 subunits. J Gen Physiol114 :203 eC213,1999
Tschritter O, Stumvoll M, Machicao F, Holzwarth M, Weisser M, Maerker E, Teigeler A, Haring H, Fritsche A: The prevalent Glu23Lys polymorphism in the potassium inward rectifier 6.2 (KIR6.2) gene is associated with impaired glucagon suppression in response to hyperglycemia. Diabetes51 :2854 eC2860,2002
Nielsen EM, Hansen L, Carstensen B, Echwald SM, Drivsholm T, Glumer C, Thorsteinsson B, Borch-Johnsen K, Hansen T, Pedersen O: The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes52 :573 eC577,2003
Shyng S, Nichols CG: Octameric stoichiometry of the KATP channel complex. J Gen Physiol110 :655 eC664,1997
Babenko AP, GC Gonzalez, Bryan J: Hetero-concatemeric KIR6.X4/SUR14 channels display distinct conductivities but uniform ATP inhibition. J Biol Chem275 :31563 eC31566,2000
Ma D, Shield JP, Dean W, Leclerc I, Knauf C, Burcelin R R, Rutter GA, Kelsey G: Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM. J Clin Invest114 :339 eC348,2004
Miki T, Nagashima K, Tashiro F, Kotake K, Yoshitomi H, Tamamoto A, Gonoi T, Iwanaga T, Miyazaki J, Seino S: Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proc Natl Acad Sci U S A95 :10402 eC10406,1998
Seghers V, Nakazaki M, DeMayo F, Aguilar-Bryan L, Bryan J: Sur1 knockout mice. A model for K(ATP) channel-independent regulation of insulin secretion. J Biol Chem275 :9270 eC9277,2000
Shiota C, Larsson O, Shelton KD, Shiota M, Efanov AM, Hoy M, Lindner J, Kooptiwut S, Juntti-Berggren L, Gromada J, Berggren PO, Magnuson MA: Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose. J Biol Chem277 :37176 eC37183,2002
Remedi M-S, Koster JC, Markova KP, Seino S, Miki T, Patton BL, McDaniel ML, Nichols CG: Diet-induced glucose intolerance in mice with decreased -cell KATP channels. Diabetes53 :3159 eC3167,2004
Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, Laakso M: A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. [see comment]. Lancet361 :301 eC307,2003
Miki T, Minami K, Zhang L, Morita M, Gonoi T, Shiuchi T, Minokoshi Y, Renaud JM, Seino S: ATP-sensitive potassium channels participate in glucose uptake in skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab283 :E1178 eCE1184,2002
Munoz A, Nakazaki M, Goodman JC, Barrios R, Onetti CG, Bryan J, Aguilar-Bryan L: Ischemic preconditioning in the hippocampus of a knockout mouse lacking SUR1-based K(ATP) channels. Stroke34 :164 eC170,2003
Inagaki N, Gonoi T, Seino S: Subunit stoichiometry of the pancreatic beta-cell ATP-sensitive K+ channel. FEBS Lett409 :232 eC236,1997
Clement, JPT, Kunjilwar K, Gonzalez G, Schwanstecher M, Panten U, Aguilar-Bryan L, Bryan J: Association and stoichiometry of K(ATP) channel subunits. Neuron18 :827 eC838,1997
Tucker SJ, Gribble FM, Zhao C, Trapp S, Ashcroft FM: Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor. Nature387 :179 eC183,1997
Tanabe K, Tucker SJ, Matsuo M, Proks P, Ashcroft FM, Seino S, Amachi T, Ueda K: Direct photoaffinity labeling of the Kir6.2 subunit of the ATP-sensitive K+ channel by 8-azido-ATP. J Biol Chem274 :3931 eC3933,1999
Drain P, Li L, Wang J: KATP channel inhibition by ATP requires distinct functional domains of the cytoplasmic C terminus of the pore-forming subunit. Proc Natl Acad Sci U S A95 :13953 eC13958,1998
Li L, Wang J, Drain P: The I182 region of k(ir)6.2 is closely associated with ligand binding in K(ATP) channel inhibition by ATP. Biophys J79 :841 eC852,2000
Trapp S, Haider S, Jones P, Sansom MS, Ashcroft FM: Identification of residues contributing to the ATP binding site of Kir6.2. EMBO J22 :2903 eC2912,2003
Tucker SJ, Gribble FM, Proks P, Trapp S, Ryder TJ, Haug T, Reimann F, Ashcroft FM: Molecular determinants of KATP channel inhibition by ATP. Embo J17 :3290 eC3296,1998
Inagaki N, Gonoi T, Clement JPT, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J: Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor [see comments]. Science270 :1166 eC1170,1995
Kennedy HJ, Pouli AE, Ainscow EK, Jouaville LS, Rizzuto R, Rutter GA: Glucose generates sub-plasma membrane ATP microdomains in single islet beta-cells. Potential role for strategically located mitochondria. J Biol Chem274 :13281 eC13291,1999
Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JPT, Boyd AER, Gonzalez G, Herrera-Sosa H, Nguy K, Bryan J, Nelson DA: Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science268 :423 eC426,1995
Inagaki N, Gonoi T, Clement JP, Wang CZ, Aguilar-Bryan L, Bryan J, Seino S: A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron16 :1011 eC1017,1996
Schwanstecher M, Sieverding C, Dorschner H, Gross I, Aguilar-Bryan L, Schwanstecher C, Bryan J: Potassium channel openers require ATP to bind to and act through sulfonylurea receptors. EMBO J17 :5529 eC5535,1998
Gribble FM, Tucker SJ, Ashcroft FM: The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. EMBO J16 :1145 eC1152,1997
Shyng S, Ferrigni T, Nichols CG: Regulation of KATP channel activity by diazoxide and MgADP: distinct functions of the two nucleotide binding folds of the sulfonylurea receptor. J Gen Physiol110 :643 eC654,1997
Shyng SL, Ferrigni T, Shepard JB, Nestorowicz A, Glaser B, Permutt MA, Nichols CG: Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy. Diabetes47 :1145 eC1151,1998
John SA, Weiss JN, Xie LH, Ribalet B: Molecular mechanism for ATP-dependent closure of the K+ channel Kir6.2. J Physiol552 :23 eC34,2003
Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA: Crystal structure of the potassium channel KirBac1.1 in the closed state. Science300 :1922 eC1926,2003
Antcliff JF, Haider S, Proks P, Sansom MS, Ashcroft FM: Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit. EMBO J24 :229 eC239,2005
Shyng SL, Cukras CA, Harwood J, Nichols CG: Structural determinants of PIP(2) regulation of inward rectifier K(ATP) channels. J Gen Physiol116 :599 eC608,2000
Cukras CA, Jeliazkova I, Nichols CG: The role of N-terminal positive charges in the activity of inward rectifier KATP channels. J Gen Physiol120 :437 eC446,2002
Enkvetchakul D, Loussouarn G, Makhina E, Shyng SL, Nichols CG: The kinetic and physical basis of K(ATP) channel gating: toward a unified molecular understanding. Biophys J78 :2334 eC2348,2000
Loussouarn G, Makhina EN, Rose T, Nichols CG: Structure and dynamics of the pore of inwardly rectifying K(ATP) channels. J Biol Chem275 :1137 eC1144,2000
Cartier EA, Shen S, Shyng SL: Modulation of the trafficking efficiency and functional properties of ATP-sensitive potassium channels through a single amino acid in the sulfonylurea receptor. J Biol Chem278 :7081 eC7090,2003
Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptacek LJ: Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell105 :511 eC519,2001
Lopes CM, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE: Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. Neuron34 :933 eC944,2002
Gloyn AL, Hashim Y, Ashcroft SJ, Ashfield R, Wiltshire S, Turner RC, the UK Prospective Diabetes Study (UKPDS 53): Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with type 2 diabetes mellitus (UKPDS 53). Diabet Med18 :206 eC212,2001
Reimann F, Tucker SJ, Proks P, Ashcroft FM: Involvement of the n-terminus of Kir6.2 in coupling to the sulphonylurea receptor. J Physiol (Lond)518 :325 eC336,1999(Joseph C. Koster, M. Alan)
CHI, congenital hyperinsulinism; FOXP3, forkhead box P3; GSIS, glucose-stimulated insulin secretion; IPF-1, insulin promoter factor 1; KATP channel, ATP-sensitive K+ channel; PIP2, phosphatidylinositol-4,5-bisphosphate; SUR1, sulfonylurea receptor-1
ABSTRACT
The ATP-sensitive K+ channel (KATP channel) senses metabolic changes in the pancreatic -cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. When KATP channels open, -cells hyperpolarize and insulin secretion is suppressed. The prediction that KATP channel "overactivity" should cause a diabetic state due to undersecretion of insulin has been dramatically borne out by recent genetic studies implicating "activating" mutations in the Kir6.2 subunit of KATP channel as causal in human diabetes. This article summarizes the emerging picture of KATP channel as a major cause of neonatal diabetes and of a polymorphism in KATP channel (E23K) as a type 2 diabetes risk factor. The degree of KATP channel "overactivity" correlates with the severity of the diabetic phenotype. At one end of the spectrum, polymorphisms that result in a modest increase in KATP channel activity represent a risk factor for development of late-onset diabetes. At the other end, severe "activating" mutations underlie syndromic neonatal diabetes, with multiple organ involvement and complete failure of glucose-dependent insulin secretion, reflecting KATP channel "overactivity" in both pancreatic and extrapancreatic tissues.
In the pancreatic -cell, the ATP-sensitive K+ channel (KATP channel) plays an essential role in coupling membrane excitability with glucose-stimulated insulin secretion (GSIS) (1). An increase in glucose metabolism leads to elevated intracellular [ATP]/[ADP] ratio, closure of KATP channels, and membrane depolarization. Consequent activation of voltage-dependent Ca2+ channels causes a rise in [Ca2+]i, which stimulates insulin release (Fig. 1). Conversely, a decrease in the metabolic signal is predicted to open KATP channels and suppress the electrical trigger of insulin secretion. Sulfonylurea drugs promote, and diazoxide suppresses, insulin secretion by binding to the regulatory sulfonylurea receptor-1 (SUR1) subunit and inhibiting, or activating, KATP channel current, respectively (2). The electrical pathway is modulated by KATP channeleCindependent mechanisms; nutrient metabolites and incretins affect secretion at various stages downstream of KATP channel (3,4), but the drug effects underscore the central role of KATP channeleCdependent regulation.
Alterations in the metabolic signal, in the sensitivity of KATP channel to metabolites, or in the number of active KATP channels, could each disrupt electrical signaling in the -cell and alter insulin release. In support of this prediction, earlier studies implicated reduced or absent KATP channel activity in the -cell as causal in congenital hyperinsulinism (CHI) in humans (5). CHI is a rare, mostly recessive, disorder characterized by constitutive insulin secretion despite low blood glucose. If left untreated, severe mental retardation and death may result. Mutations in KATP channel that reduce channel expression, decrease stimulation of the channel by MgADP, or abolish channel activity account for a majority of all CHI mutations (6,7,8,9). Conversely, mutations that result in "overactive" channels should decrease membrane excitability and impair glucose sensing by the -cell. In this scenario, insulin secretion will be reduced and a diabetic phenotype is predicted. A clear picture is now emerging from both animal and human studies that such KATP channel mutations can indeed cause diabetes. The first part of this review will detail the rapidly emerging clinical evidence for involvement of KATP channel mutations in neonatal and type 2 diabetes and the cellular basis of the disease. The second part will consider the structure-function relationships of the KATP channel and molecular mechanisms that underlie diabetes in which mutations in KATP are causal.
Part 1: -cell KATP channel and diabetes: the emerging genetic and clinical picture
Mutations in Kir6.2 underlie neonatal diabetes.
Given the above paradigm, any gain of KATP channel function is expected to suppress GSIS. This prediction was originally confirmed by the striking neonatal diabetic phenotype of two different genetic models: 1) mice with targeted disruption of the pancreatic -cell glucokinase gene (10) and 2) transgenic mice expressing -cell KATP channels with decreased sensitivity to inhibitory ATP (i.e., "overactive" KATP channel) (11). In each case, acute neonatal hyperglycemia together with ketoacidosis, leading to death within a few days, was observed. In the latter model (Fig. 2A), blood insulin is at or below the level of detection but insulin is clearly present in the pancreas (11). In each case, overactive KATP channel activity, with a failure to switch on insulin secretion, is the logical underlying mechanism; this is due to altered metabolic signal in the former (12) and insensitivity to the normal metabolic signal in the latter (11).
The obvious prediction of these mouse models is that genetically induced ATP insensitivity of -cell KATP channels could underlie impaired insulin release and neonatal diabetes in humans (13,14). Rare in occurrence (1:400,000 births), neonatal diabetes is usually diagnosed within the first 3 months of life and relies on insulin administration to treat the hyperglycemia (15). In transient neonatal diabetes, which is milder, hyperglycemia usually resolves within 18 months, whereas the permanent form requires insulin treatment for life. Until recently, the cause of the majority of permanent neonatal diabetes cases has remained unknown. Homozygous and compound heterozygous mutations in glucokinase, the rate-limiting enzyme of glucose metabolism in islet cells, cause isolated permanent neonatal diabetes and account for a minority of cases (at least six families reported to date) (16,17). Similarly, compound heterozygous or homozygous mutations in insulin promoter factor 1 (IPF-1), an essential transcriptional regulator of pancreatic development, underlie a fewer number of cases (18,19). Other rare forms of permanent neonatal diabetes are associated with multiple deficiencies. These include Wolcott-Rallison syndrome, characterized by infancy-onset diabetes along with growth and mental retardation and caused by mutations in EIF2AK3, a regulator of protein synthesis (20,21). In addition, defects of forkhead box P3 (FOXP3) underlie IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, which also includes neonatal-onset diabetes (22). While defects in glucokinase and KATP channel are predicted to impair glucose sensing of the -cell, leading to suppressed insulin release, mutations in IPF-1 and FOXP3 underlie decreased -cell mass; IPF-1 through impaired pancreatic development and FOXP3 through autoimmune destruction of pancreatic islets (23,24). In contrast to permanent neonatal diabetes, a majority of transient neonatal diabetes cases are attributable to paternal imprinting at chromosome 6q24 (25). Two candidate genes have been identified: ZAC (zinc finger protein that regulates apoptosis and cell-cycle arrest) and HYAMI (hydatidiform mole-associated and imprinted transcript), an untranslated mRNA of unknown function.
Recent genetic studies demonstrate that heterozygous mutations in KCNJ11, encoding the Kir6.2 subunit of the KATP channel, underlie neonatal diabetes in humans, accounting for both permanent neonatal diabetes (26eC31), in which type 1 autoantibodies are absent, and relapsing transient neonatal diabetes, in which chromosome 6 abnormalities were excluded (32,33). Both de novo appearance of Kir6.2 mutations and familial transmission have been reported (26eC31). Significantly, in all examined families, neonatal diabetes was observed only in individuals carrying the Kir6.2 mutations and not in other family members. Interestingly, in a subgroup of patients carrying Kir6.2 mutations, permanent neonatal diabetes is part of a larger syndrome that often includes marked developmental delay in motor intellectual and social skills, muscle weakness, dysmorphic features, and epilepsy (27,29,30). Despite normal-sized cortex and cerebellum, a majority of patients with syndromic permanent neonatal diabetes also display language and social development that is delayed from 5 to 48 months (27). There appears to be no correlation between the age of diagnosis and the severity of the permanent neonatal diabetes (syndromic versus nonsyndromic). As Kir6.2 represents the pore-forming subunit of KATP channels in skeletal muscle and in neurons throughout the brain (34,35), differentially overactive KATP channels in extrapancreatic tissue can potentially account for neurological disorders associated with this subgroup of patients through as-yet-to-be-defined mechanisms.
Neonatal diabetic subjects with Kir6.2 mutations demonstrate varying levels of C-peptide (27,31eC33,36) consistent with a varying degree of -cell dysfunction and likely accounting for the variable hyperglycemia often observed with neonatal diabetes. Consistent with a defect at the level of KATP channel, affected patients carrying R201 mutations did not secrete insulin in response to glucose or glucagon but did in response to sulfonylurea (tolbutamide), albeit at subnormal levels (Fig. 2B) (27,30). Importantly, several patients have now been weaned from insulin onto glibenclamide therapy, and at 1- to 6-month follow-ups, blood glucose has been well controlled without insulin supplement (31,36). In many cases, however, the oral dosage of sulfonylureas significantly exceeds (by several-fold) the doses commonly used to treat type 2 diabetes (36,37). Consistent with this clinical observation, the neonatal diabeteseCcausing mutations in Kir6.2 are frequently associated with a concomitant decrease in sensitivity of the KATP channel to sulfonylureas (27,38,39), which may underlie the increased therapeutic dosages.
As additional mutations are uncovered, it is becoming clear that the temporal presentation of the disease can be quite variable. One patient was diagnosed at only 26 weeks of age (27) and another at 5 years (32). Within a single pedigree, one Kir6.2 mutation (C42R) is shown to underlie transient neonatal diabetes, childhood-onset diabetes, as well an apparently type 2 diabetes, all in different carriers (33). Such late presentation suggests that the disease may become apparent at much later ages than typically ascribed, consistent with the notion that the mildest forms of the disease may not manifest until adulthood. This raises the additional possibility that if the disease manifests postnatally, it may be misdiagnosed as type 1 diabetes. So far, however, screening of children diagnosed with type 1 diabetes before 2 years of age, and lacking predisposing HLA genotypes, has failed to demonstrate a significant number of KCNJ11 mutations (28).
Polymorphisms of Kir6.2 predispose to adult-onset diabetes.
Numerous studies have now examined the association of KATP channel polymorphisms with late-onset type 2 diabetes (40eC44). By suppressing excitability, KATP channel polymorphisms that increase channel activity could, in combination with other environmental and genetic factors, contribute to chronically impaired -cell function. In the face of insulin resistance, this is expected to exacerbate the hyperglycemic state. Although results from initial studies are conflicting (45,46), large-scale association studies and meta-analyses have now identified the E23K polymorphism in KCNJ11 as a slight, but significant, risk factor in the complex development of type 2 diabetes (42,44,47eC50). However, given the high allelic frequency of E23K in the general population (frequency of heterozygous EK genotype = 47%; homozygous KK genotype = 12%), the polymorphism is likely to represent a large population-attributable risk (41,48,51,52). Importantly, a recent haplotype analysis of the Kir6.2/SUR1 gene region has demonstrated a strong allelic association of E23K in Kir6.2 with a polymorphism in SUR1 (A1369S), raising the possibility that E23K alone may not entirely account for the reported association with type 2 diabetes (49).
Cellular basis of KATP channel diabetes.
Recombinant expression of mutant channels indicates that both the type 2eCassociated polymorphism (E23K) and neonatal diabeteseCassociated Kir6.2 mutations result in reduced sensitivity to intracellular ATP, either by reducing ATP affinity per se or indirectly via an increase in the intrinsic open-state stability (27,38,39,51,53) (see below). At the cellular level, an important question is: Just how much change in ATP sensitivity is necessary to cause significant impairment of insulin secretion The diabetic phenotype of transgenic mice expressing "overactive" KATP channels in -cells predicted the correlate disease in humans and is a potentially relevant model (11). These mice express Kir6.2 subunits with truncated NH2-termini, which causes a 10-fold reduction of ATP sensitivity in heterologously expressed channels. Transgenic F1 mice from four of five founder lines expressing the truncated channels were severely hyperglycemic, and hypoinsulinemic, and died as neonates by day 5, most likely from acute ketoacidosis (Fig. 2A). Electrophysiology confirmed functional expression of KATP channels with reduced ATP sensitivity, but only approximately fourfold relative to wild type.
Heterologously expressed Kir.2[E23K]-SUR1 channels exhibit even more modest 2- and 1.5-fold reductions in ATP sensitivity for homozygous (Kir6.2[E23K]) and heterozygous (Kir6.2[E23K] + Kir6.2wt) channels, respectively (51 and J.C.K., unpublished observations: K1/2 [ATP] for Kir6.2wt = 10.7 ± 1.9 e蘭ol/l, Kir6.2[E23K] = 17.6 ± 0.9 e蘭ol/l [expressed in COSm6 cells]), as well as enhanced MgADP stimulation (51,52,53,54). E23K is in linkage disequilibrium with another Kir6.2 polymorphism, I337V, which itself has no reported effect on channel activity (51,53). Another study reported no reduction of ATP sensitivity of E23K/I337V channels, but instead showed enhanced stimulatory effects of palmitoyl-CoA on E23K/I337V mutant Kir6.2 channels (55). As discussed below, a small increase in intrinsic open-state stability can underlie a decrease in apparent ATP sensitivity, as well as an increase in sensitivity to activator molecules (51eC54,56). It seems likely that increased palmitoyl-CoA sensitivity in the latter study, as well as increased MgADP sensitivity and reduced ATP sensitivity in the previous study, all reflect just such an increase. In all cases, the net effect will be reduced glucose sensing by the -cell, and, in support, a small effect of the E23K variant on insulin release was observed during intravenous and oral glucose tolerance tests (43,57,58).
E23K also has a strong allelic association with a SUR1 polymorphism (A1369S), raising the possibility that the SUR1 variant may influence, or account for, altered channel activity (49). The effect of the A1369S polymorphism on channel activity is not known (51,55), but the possibility should be acknowledged that alone or in combination with E23K, it contributes to altered ATP sensitivity. (In our unpublished studies of E23K, reconstituted KATP channels carried both the I337V and A1369S polymorphisms.)
What of the ATP sensitivity of different neonatal diabetes mutants Gloyn et al. (27) initially showed an 35-fold loss of ATP sensitivity for homozygous R201H mutant channels, but almost no shift in a 1:1 mixture of wild-type and R201H mutant subunits, expected to recapitulate the heterozygous state of the disease. Assuming a 1:1 expression and random assembly, 16 different subunit arrangements are formally possible, making the analysis of mixed expression very complex (51,53,59,60). However, as acknowledged, 1 of 16 of the expressed channels are expected to be pure mutant, and this alone could give rise to significant currents at physiological [ATP]/[ADP] ratios. Other mutations (Q52R, I296L I182V, V59G, V59M, Y330C, and F333I) have now been analyzed, demonstrating shifts in ATP sensitivity of up to 1,000-fold for homozygous V59G and I296L mutant channels (38,39). Again, much lesser shifts were observed in heterozygous expression, but, without analyzing each subunit combination separately, it remains speculative as to exactly what channel activity can be expected in vivo.
Nonelectrical consequences of altered KATP channel activity.
At this juncture, we cannot preclude nonelectrical secondary mechanisms underlying KATP channeleCinduced diabetes. Mice with overactive -cell KATP channels are profoundly diabetic within a few days of birth (11). Morphologically, the size, distribution, and architecture of the islets are unperturbed at the earliest stages of diabetes (days 1eC3), but collapse of islet architecture, with diffuse distribution of the - and -cells throughout the pancreas, was observed at later stages (after day 3). A similar mechanistic progression may occur in KATP channeleCinduced permanent neonatal diabetes and may underlie some of the reduced sulfonylurea-sensitive insulin release (27). Moreover, a recent transgenic study overexpressing the transient neonatal diabetes locus (6q24) implicated fluctuations in -cell mass and insulin content in the progression of transient neonatal diabetes from the neonatal diabetic phase into remission and ultimately to late-onset diabetes (61). If a similar pathophysiology occurs in transient neonatal diabetes patients carrying Kir6.2 mutations, this would be consistent with secondary, nonelectrical consequences of altered -cell KATP channel activity. Secondary complications do occur in the converse disease progression resulting from reduced KATP channel density. Transgenic mice lacking KATP channels in 70% of -cells, due to -cell expression of dominant-negative Kir6.2 transgene, hypersecrete throughout as adults (14), but mice completely lacking KATP channels are reportedly hyperinsulinemic as neonates and then progress to reduced GSIS and glucose intolerance as adults (62eC64). Importantly, when exposed to a high-fat diet, both Kir6.2eC/eC mice and Kir6.2[AAA] transgenic mice progress rapidly to severely undersecreting diabetes (65). While these hyperexcitable mice, with reduced KATP channel activity, thus have a very different response to those with overactive KATP channels, they do suggest that profound nonelectrical consequences can follow an initial electrical disturbance.
In addition to Kir6.2 defects, loss or reduction of KATP channel activity can also occur due to loss-of-function mutations of the regulatory SUR1 subunit; such mutations are the most frequent cause of CHI (5). Clinical data indicate that CHI patients carrying SUR1 mutations can also progress to glucose intolerance and, in some cases, overt diabetes (66).
Finally, noneC-cell mechanisms must be considered. Kir6.2 is the pore-forming subunit of -cell, muscular, and neuronal KATP channels (34). In skeletal muscle, or in neurons, overactive KATP channel could potentially underlie the muscle weakness reported in syndromic permanent neonatal diabetes (27,29). Glucose uptake by skeletal muscle and adipose may also be dependent on KATP channel activity (67), and overactivity in syndromic permanent neonatal diabetes could compromise this function. In neurons, metabolic sensing is altered with loss of KATP channels (35,68). Again, the unknown consequences of KATP channel overactivity could underlie developmental defects that are also observed in syndromic permanent neonatal diabetes (27,29). Complete understanding of the mechanisms by which Kir6.2 mutations cause neonatal diabetes will require mechanistic molecular analysis of disease-causing mutations (32,33,38,39), generation of transgenic mouse models of neonatal diabetes (11), and analysis of virally infected -cells or insulinoma cell lines expressing altered KATP channel.
Part 2: KATP channeleCdependent diabetes: the molecular defects
The KATP channel: structure and function.
Structurally, the pancreatic KATP channel consists of two unrelated subunits: a sulfonylurea receptor (the SUR1 isoform) that is a member of the ABC transporter family and a potassium channel subunit (Kir6.2) that forms the central ion-conducting pathway (Fig. 3A). The mature KATP channel exists as an octamer of Kir6.2 and SUR1 subunits in a 4:4 stoichiometry (Fig. 3B) (59,69,70). The signature ATP inhibition of the channel results from binding to the pore-forming Kir6.2 subunit (71,72,73,74,75,76). Importantly, the inhibitory concentration of ATP causing half-maximal channel inhibition is in the micromolar range (K1/2[ATP] 10 e蘭ol/l for native KATP channel) (77), yet cytosolic [ATP] is in the millimolar range (1eC5 mmol/l) and changes little in the presence of high glucose (78). This observation implicates MgADP, rather than ATP, as the primary physiological regulator of channel activity. Through interaction with SUR1, MgADP "stimulates" channel activity by countering ATP inhibition (8,79eC83). SUR1 mutations that abolish MgADP action, but do not alter ATP sensitivity, also abolish channel activity in vivo and underlie CHI (8,84). It should be pointed out, however, that despite the essential regulatory role of MgADP, ATP sensitivity of the channel will still be critical in determining the magnitude of KATP channel current. For a given [MgADP], KATP channel mutations that decrease ATP sensitivity will enhance absolute currents in the physiologic range of ATP, and the net effect of enhanced KATP channel current is a decrease in -cell excitability.
Molecular mechanisms of KATP channeleCinduced neonatal diabetes.
Multiple permanent neonatal diabetes mutations have now been identified in Kir6.2 (Fig. 3C). To date, the most frequently mutated residues are R201 and V59; heterozygous mutations of these residues have been detected in multiple probands (27,29,30). Y330C accounted for three cases of permanent neonatal diabetes (28,30), whereas K170 substitutions accounted for two permanent neonatal diabetes cases (K170N and K170R) (29). Q52R, I296L, R50P, F33I, and E322K have all been found in one proband each (28,29,31). Kir6.2 mutations causing transient neonatal diabetes include G53, I182, and C42 (32,33).
These mutations could reduce ATP sensitivity 1) directly by decreasing the affinity of the ATP-binding pocket for the nucleotide, 2) indirectly by an increase in the intrinsic stability of the open state of the channel, or 3) indirectly by an increased sensitivity to the counteractivation by MgADP or by phosphatidylinositol-4,5-bisphosphate (PIP2) or other phospholipids. Consistent with a direct effect on binding, R50, I182, Y330, F333, and R201 have all previously been implicated as putative ATP-binding residues in Kir6.2 (27,74,85). Modeling of the COOH-terminus of Kir6.2, based on homology with the crystal structure of the related Kir3.1, predicts that I182 resides in a hydrophobic pocket that coordinates the adenine ring of ATP (75), while positively charged R201 and R50 are predicted to interact electrostatically with the phosphate tail of ATP (75,85,86). Both Y330 and F333 also predicted to lie close to the phosphate tail in the binding pocket (87).
Fully consistent with the above structural model of the ATP-binding pocket, functional characterization now demonstrates a significant decrease in the ATP sensitivities of these mutants (27,32,38,39). In the case of I182V, R201C, R201H, and F333I, these mutations do not alter gating of the channel and are, therefore, likely to directly alter ATP affinity at the binding pocket. A few additional residues in the NH2- and COOH-terminus are also likely to be involved in ATP binding (71,73,75,76,88,89), and we speculate that substitutions at these residues would also be disease causing.
With respect to indirect channel mechanisms, mutations that alter channel gating in the absence of ATP can have profound effects on apparent ATP sensitivity (73,76,90). Such mutations are found throughout the Kir6.2 subunit. In some cases, these "open-state stability" mutations are located in transmembrane segments, a significant distance from the putative ATP-binding domain (86,91). Many, including E23K, stabilize the open state of the channel, thereby increasing the channel opening independently of ATP and indirectly reducing the apparent affinity for ATP (51,54). The reported loss of ATP sensitivity coupled with high open probability in the Q52R, C42R, Y330C, I1296L, and V59G mutations suggests such a mechanism in these disease mutations (38,39). Consistent with the functional interpretation, Q52 and V59 are located within the predicted slide helix region of Kir6.2 and may regulate channel gating by coupling the ATP-binding site physically to the gating region (75,86). The second transmembrane helices in each of the Kir6.2 subunits converge at the so-called "bundle crossing" and may form the ligand-controlled gate (Fig. 3C) (86,91). An effect on the gate region of the channel might then explain the diabetes-causing effects of mutations at residue K170 (K170N and K170R; Fig. 3) within this region (29).
Since all proteins are evolutionarily tailored to generate specific functions, it follows that disease-causing mutations are most likely to cause loss of the specific function. In the present context, loss of high-affinity inhibition by ATP, either directly or indirectly, is thus the most likely mechanism to underlie the net "gain of function" that underlies neonatal diabetes. However, it is conceivable that spontaneous mutations may also cause an increase in an activating function, such as an increase in the MgADP affinity of SUR1. Alternately, mutations could increase the affinity for PIP2 or other phospholipids, which serve as activators of the channel. In this regard, one or two rare mutations engineered into SUR1 (83,92) increase activation by MgADP, and they could potentially appear spontaneously. Mutations of Kir2.1, a related K channel subunit, underlie Andersen’s syndrome, which is characterized by dysmorphic facial features, epilepsy, and cardiac arrhythmias (93,94). It is argued that these mutations alter Kir2.1 channel function by modulating the phospholipids sensitivity (94). Similarly, many mutations in KATP are likely to affect apparent PIP2 sensitivity by changes in intrinsic open-state stability (54) or by change in affinity. Although none have been reported, it remains possible that neonatal diabetes could also result from gain of function due to an increased affinity for PIP2.
Perspectives and prospects.
The 10-year effort that first yielded the molecular basis of KATP channel activity (77,79) permitted the generation of animal models of channel dysfunction (11) and paved the way to genetic determination of predisposing polymorphisms in type 2 diabetes (41,45,46,95) and disease-causing mutations in both CHI (5) and neonatal diabetes (27,29,33). This in turn has led to an immediate understanding of the likely molecular basis of permanent neonatal diabetes and to improved therapy (31,36). This progression is a dramatic demonstration of the power of multidisciplinary biology in disease analysis. The current results elucidate the molecular basis of a traumatic neonatal disease and exciting possibilities for improvement in treatment options.
KATP channel may be involved in a whole spectrum of diabetes. For the E23K polymorphism, the effect on nucleotide sensitivity is modest, and only in the proper genetic and environmental background may channel overactivity appreciably influence -cell function. Mutations resulting in greater gain of function may still be found to underlie childhood diabetes, while mutations that result in more significant gain of function are likely to give rise to an earlier and more severe form of diabetes, as in permanent neonatal diabetes. In the most severe cases, KATP channel overactivity in extrapancreatic tissue likely contributes to multiorgan syndromic permanent neonatal diabetes. Sulfonylureas may provide dramatic improvement in therapeutic options for neonatal diabetes (27,31,33), but the sulfonylurea-desensitizing effect of open-stateeCstabilizing mutations (39,56,96) and the possibility of secondary nonelectrical consequences heed caution regarding whether this is a panacea.
ACKNOWLEDGMENTS
The authors’ experimental work has been supported by National Institutes of Health Grant DK69445 (to C.G.N.) and Washington University Diabetes Research and Training Center Pilot and Feasibility Award DK20579 (to J.C.K.).
REFERENCES
Ashcroft FM, Rorsman P: ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion. Biochem Soc Trans18 :109 eC111,1990
Aguilar-Bryan L, Bryan J: Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr Rev20 :101 eC135,1999
Aizawa T, Komatsu M, Asanuma N, Sato Y, Sharp GW: Glucose action ‘beyond ionic events’ in the pancreatic beta cell. Trends Pharmacol Sci19 :496 eC499,1998 [erratum in Trends Pharmacol Sci20:124, 1999]
Komatsu M, Sato Y, Aizawa T, Hashizume K: KATP channel-independent glucose action: an elusive pathway in stimulus-secretion coupling of pancreatic beta-cell (Review). Endocr J48 :275 eC288,2001
Huopio H, Shyng SL, Otonkoski T, Nichols CG: K(ATP) channels and insulin secretion disorders (Review). Am J Physiol Endocrinol Metab283 :E207 eCE216,2002
Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J: Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science268 :426 eC429,1995
Nestorowicz A, Glaser B, Wilson BA, Shyng SL, Nichols CG, Stanley CA, Thornton PS, Permutt MA: Genetic heterogeneity in familial hyperinsulinism. Hum Mol Genet7 :1119 eC1128,1998 [erratum in Hum Mol Genet7:1527, 1998]
Nichols CG, Shyng SL, Nestorowicz A, Glaser B, Clement JP 4th, Gonzalez G, Aguilar-Bryan L, Permutt MA, Bryan J: Adenosine diphosphate as an intracellular regulator of insulin secretion. Science272 :1785 eC1787,1996
Cartier EA, Conti LR, Vandenberg CA, Shyng SL: Defective trafficking and function of KATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent hyperinsulinemic hypoglycemia of infancy. Proc Natl Acad Sci U S A98 :2882 eC2887,2001
Terauchi Y, Sakura H, Yasuda K, Iwamoto K, Takahashi N, Ito K, Kasai H, Suzuki H, Ueda O, Kamada N, et al.: Pancreatic beta-cell-specific targeted disruption of glucokinase gene: diabetes mellitus due to defective insulin secretion to glucose. J Biol Chem270 :30253 eC30256,1995
Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CG: Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell100 :645 eC654,2000
Sakura H, Ashcroft SJ, Terauchi Y, Kadowaki T, Ashcroft FM: Glucose modulation of ATP-sensitive K-currents in wild-type, homozygous and heterozygous glucokinase knock-out mice. Diabetologia41 :654 eC659,1998
Ashcroft FM, Rorsman P: Type 2 diabetes mellitus: not quite exciting enough (Review). Hum Mol Genet13 :R21 eCR31,2004
Nichols CG, Koster JC: Diabetes and insulin secretion: whither KATP (Review). Am J Physiol Endocrinol Metab283 :E403 eCE412,2002
Polak M, Shield J: Neonatal and very-early-onset diabetes mellitus. Semin Neonatol9 :59 eC65,2004
Njolstad PR, Sovik O, Cuesta-Munoz A, Bjorkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI: Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med344 :1588 eC1592,2001
Njolstad PR, Sagen JV, Bjorkhaug L, Odili S, Shehadeh N, Bakry D, Sarici SU, Alpay F, Molnes J, Molven A, Sovik O, Matschinsky FM: Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes52 :2854 eC2860,2003
Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF: Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet15 :106 eC110,1997
Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A, Jornayvaz FR, Theintz GE, Michielin O, Melloul D, Philippe J: Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J Clin Endocrinol Metab88 :4398 eC4406,2003
Biason-Lauber A, Lang-Muritano M, Vaccaro T, Schoenle EJ: Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. Diabetes51 :2301 eC2305,2002
Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C: EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet25 :406 eC409,2000
Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD: The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet27 :20 eC21,2001
Roberts J, Searle J: Neonatal diabetes mellitus associated with severe diarrhea, hyperimmunoglobulin E syndrome, and absence of islets of Langerhans. Pediatr Pathol Lab Med15 :477 eC483,1995
Jonsson J, Carlsson L, Edlund T, Edlund H: Insulin-promoter-factor 1 is required for pancreas development in mice. Nature371 :606 eC609,1994
Gardner RJ, Mackay DJ, Mungall AJ, Polychronakos C, Siebert R, Shield JP, Temple IK, Robinson DO: An imprinted locus associated with transient neonatal diabetes mellitus. Hum Mol Genet9 :589 eC596,2000
Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, Costa T, Temple IK, Hattersley AT, Ellard S: Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab89 :3932 eC3935,2004
Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT: Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med350 :1838 eC1849,2004
Edghill EL, Gloyn AL, Gillespie KM, Lambert AP, Raymond NT, Swift PG, Ellard S, Gale EA, Hattersley AT: Activating mutations in the KCNJ11 gene encoding the ATP-sensitivie K+ channel subunit Kir6.2 are rare in clinically defined type 1 diabetes diagnosed before 2 years. Diabetes53 :2998 eC3001,2004
Massa O, Iafusco D, D’Amato E, Gloyn AL, Hattersley AT, Pasquino B, Tonini G, Dammacco F, Zanette G, Meschi F, Porzio O, Bottazzo G, Crino A, Lorini R, Cerutti F, Vanelli M, Barbetti F, the Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetology: KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat25 :22 eC27,2005
Vaxillaire M, Populaire C, Busiah K, Cave H, Gloyn AL, Hattersley AT, Czernichow P, Froguel P, Polak M: Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes53 :2719 eC2722,2004
Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Sovik O, Njolstad PR: Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes53 :2713 eC2718,2004
Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JP, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT: Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet14 :925 eC934,2005
Yorifuji T, Nagashima K, Kurokawa K, Kawai M, Oishi M, Akazawa Y, Hosokawa M, Yamada Y, Inagaki N, Nakahata T: The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J Clin Endocrinol Metab90 :3174 eC3178,2005
Seino S, Iwanaga T, Nagashima K, Miki T: Diverse roles of KATP channels learned from Kir6.2 genetically engineered mice. Diabetes49 :311 eC318,2000
Yamada K, Ji JJ, Yuan H, Miki T, Sato S, Horimoto N, Shimizu T, Seino S, Inagaki N: Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. Science292 :1543 eC1546,2001
Zung A, Glaser B, Nimri R, Zadik Z: Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J Clin Endocrinol Metab89 :5504 eC5507,2004
Codner E, Flanagan S, Ellard S, Garcia H, Hattersley AT: High-dose glibenclamide can replace insulin therapy despite transitory diarrhea in early-onset diabetes caused by a novel R201L Kir6.2 mutation (Letter). Diabetes Care28 :758 eC759,2005
Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM: Molecular basis of Kir6.2 mutations associated with neonatal diabetes plus neurological features. Proc Natl Acad Sci U S A101 :17539 eC17544,2004
Koster JC, Remedi MS, Dao C, Nichols CG: ATP and sulfonylurea sensitivity of mutant ATP-sensitive K+ channels in neonatal diabetes: implications for pharmacogenomic therapy. Diabetes54 :2645 eC2654,2005
Inoue H, Ferrer J, Welling CM, Elbein SC, Hoffman M, Mayorga R, Warren-Perry M, Zhang Y, Millns H, Turner R, Province M, Bryan J, Permutt MA, Aguilar-Bryan L: Sequence variants in the sulfonylurea receptor (SUR) gene are associated with NIDDM in Caucasians. Diabetes45 :825 eC831,1996
Hani EH, Boutin P, Durand E, Inoue H, Permutt MA, Velho G, Froguel P: Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians. Diabetologia41 :1511 eC1515,1998
Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM: Large-scale association studies of variants in genes encoding the pancreatic -cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes52 :568 eC572,2003
’t Hart LM, van Haeften TW, Dekker JM, Bot M, Heine RJ, Maassen JA: Variations in insulin secretion in carriers of the E23K variant in the KIR6.2 subunit of the ATP-sensitive K+ channel in the -cell. Diabetes51 :3135 eC3138,2002
Barroso I, Luan J, Middelberg RP, Harding AH, Franks PW, Jakes RW, Clayton D, Schafer AJ, O’Rahilly S, Wareham NJ: Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biology1 :E20 ,2003
Sakura H, Wat N, Horton V, Millns H, Turner RC, Ashcroft FM: Sequence variations in the human Kir6.2 gene, a subunit of the beta-cell ATP-sensitive K-channel: no association with NIDDM in while Caucasian subjects or evidence of abnormal function when expressed in vitro. Diabetologia39 :1233 eC1236,1996
Inoue H, Ferrer J, Warren-Perry M, Zhang Y, Millns H, Turner RC, Elbein SC, Hampe CL, Suarez BK, Inagaki N, Seino S, Permutt MA: Sequence variants in the pancreatic islet -cell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM. Diabetes46 :502 eC507,1997
Laukkanen O, Pihlajamaki J, Lindstrom J, Eriksson J, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Tuomilehto J, Uusitupa M, Laakso M, the Finnish Diabetes Prevention Study Group: Polymorphisms of the SUR1 (ABCC8) and Kir6.2 (KCNJ11) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. J Clin Endocrinol Metab89 :6286 eC6290,2004
Love-Gregory L, Wasson J, Lin J, Skolnick G, Suarez B, Permutt MA: E23K single nucleotide polymorphism in the islet ATP-sensitive potassium channel gene (Kir6.2) contributes as much to the risk of type II diabetes in Caucasians as the PPARgamma Pro12Ala variant (Letter). Diabetologia46 :136 eC137,2003
Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D: Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes53 :1360 eC1368,2004
Riedel MJ, Steckley DC, Light PE: Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes (Review). Hum Genet116 :133 eC145,2005
Schwanstecher C, Meyer U, Schwanstecher M: KIR6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic -cell ATP-sensitive K+ channels. Diabetes51 :875 eC879,2002
Schwanstecher C, Schwanstecher M: Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2 diabetes. Diabetes51 (Suppl. 3) :S358 eCS362,2002
Schwanstecher C, Neugebauer B, Schulz M, Schwanstecher M: The common single nucleotide polymorphism E23K in KIR6.2 sensitizes pancreatic -cell ATP-sensitive potassium channels toward activation through nucleoside diphosphates. Diabetes51 (Suppl. 3) :S363 eCS367,2002
Enkvetchakul D, Nichols CG: Gating mechanism of KATP channels: function fits form. J Gen Physiol122 :471 eC480,2003
Riedel MJ, Boora P, Steckley D, de Vries G, Light PE: Kir6.2 polymorphisms sensitize -cell ATP-sensitive potassium channels to activation by acyl CoAs: a possible cellular mechanism for increased susceptibility to type 2 diabetes Diabetes52 :2630 eC2635,2003
Koster JC, Sha Q, Nichols CG: Sulfonylurea and K(+)-channel opener sensitivity of K(ATP) channels: functional coupling of Kir6.2 and SUR1 subunits. J Gen Physiol114 :203 eC213,1999
Tschritter O, Stumvoll M, Machicao F, Holzwarth M, Weisser M, Maerker E, Teigeler A, Haring H, Fritsche A: The prevalent Glu23Lys polymorphism in the potassium inward rectifier 6.2 (KIR6.2) gene is associated with impaired glucagon suppression in response to hyperglycemia. Diabetes51 :2854 eC2860,2002
Nielsen EM, Hansen L, Carstensen B, Echwald SM, Drivsholm T, Glumer C, Thorsteinsson B, Borch-Johnsen K, Hansen T, Pedersen O: The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes52 :573 eC577,2003
Shyng S, Nichols CG: Octameric stoichiometry of the KATP channel complex. J Gen Physiol110 :655 eC664,1997
Babenko AP, GC Gonzalez, Bryan J: Hetero-concatemeric KIR6.X4/SUR14 channels display distinct conductivities but uniform ATP inhibition. J Biol Chem275 :31563 eC31566,2000
Ma D, Shield JP, Dean W, Leclerc I, Knauf C, Burcelin R R, Rutter GA, Kelsey G: Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM. J Clin Invest114 :339 eC348,2004
Miki T, Nagashima K, Tashiro F, Kotake K, Yoshitomi H, Tamamoto A, Gonoi T, Iwanaga T, Miyazaki J, Seino S: Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proc Natl Acad Sci U S A95 :10402 eC10406,1998
Seghers V, Nakazaki M, DeMayo F, Aguilar-Bryan L, Bryan J: Sur1 knockout mice. A model for K(ATP) channel-independent regulation of insulin secretion. J Biol Chem275 :9270 eC9277,2000
Shiota C, Larsson O, Shelton KD, Shiota M, Efanov AM, Hoy M, Lindner J, Kooptiwut S, Juntti-Berggren L, Gromada J, Berggren PO, Magnuson MA: Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose. J Biol Chem277 :37176 eC37183,2002
Remedi M-S, Koster JC, Markova KP, Seino S, Miki T, Patton BL, McDaniel ML, Nichols CG: Diet-induced glucose intolerance in mice with decreased -cell KATP channels. Diabetes53 :3159 eC3167,2004
Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, Laakso M: A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. [see comment]. Lancet361 :301 eC307,2003
Miki T, Minami K, Zhang L, Morita M, Gonoi T, Shiuchi T, Minokoshi Y, Renaud JM, Seino S: ATP-sensitive potassium channels participate in glucose uptake in skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab283 :E1178 eCE1184,2002
Munoz A, Nakazaki M, Goodman JC, Barrios R, Onetti CG, Bryan J, Aguilar-Bryan L: Ischemic preconditioning in the hippocampus of a knockout mouse lacking SUR1-based K(ATP) channels. Stroke34 :164 eC170,2003
Inagaki N, Gonoi T, Seino S: Subunit stoichiometry of the pancreatic beta-cell ATP-sensitive K+ channel. FEBS Lett409 :232 eC236,1997
Clement, JPT, Kunjilwar K, Gonzalez G, Schwanstecher M, Panten U, Aguilar-Bryan L, Bryan J: Association and stoichiometry of K(ATP) channel subunits. Neuron18 :827 eC838,1997
Tucker SJ, Gribble FM, Zhao C, Trapp S, Ashcroft FM: Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor. Nature387 :179 eC183,1997
Tanabe K, Tucker SJ, Matsuo M, Proks P, Ashcroft FM, Seino S, Amachi T, Ueda K: Direct photoaffinity labeling of the Kir6.2 subunit of the ATP-sensitive K+ channel by 8-azido-ATP. J Biol Chem274 :3931 eC3933,1999
Drain P, Li L, Wang J: KATP channel inhibition by ATP requires distinct functional domains of the cytoplasmic C terminus of the pore-forming subunit. Proc Natl Acad Sci U S A95 :13953 eC13958,1998
Li L, Wang J, Drain P: The I182 region of k(ir)6.2 is closely associated with ligand binding in K(ATP) channel inhibition by ATP. Biophys J79 :841 eC852,2000
Trapp S, Haider S, Jones P, Sansom MS, Ashcroft FM: Identification of residues contributing to the ATP binding site of Kir6.2. EMBO J22 :2903 eC2912,2003
Tucker SJ, Gribble FM, Proks P, Trapp S, Ryder TJ, Haug T, Reimann F, Ashcroft FM: Molecular determinants of KATP channel inhibition by ATP. Embo J17 :3290 eC3296,1998
Inagaki N, Gonoi T, Clement JPT, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J: Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor [see comments]. Science270 :1166 eC1170,1995
Kennedy HJ, Pouli AE, Ainscow EK, Jouaville LS, Rizzuto R, Rutter GA: Glucose generates sub-plasma membrane ATP microdomains in single islet beta-cells. Potential role for strategically located mitochondria. J Biol Chem274 :13281 eC13291,1999
Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JPT, Boyd AER, Gonzalez G, Herrera-Sosa H, Nguy K, Bryan J, Nelson DA: Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science268 :423 eC426,1995
Inagaki N, Gonoi T, Clement JP, Wang CZ, Aguilar-Bryan L, Bryan J, Seino S: A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron16 :1011 eC1017,1996
Schwanstecher M, Sieverding C, Dorschner H, Gross I, Aguilar-Bryan L, Schwanstecher C, Bryan J: Potassium channel openers require ATP to bind to and act through sulfonylurea receptors. EMBO J17 :5529 eC5535,1998
Gribble FM, Tucker SJ, Ashcroft FM: The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. EMBO J16 :1145 eC1152,1997
Shyng S, Ferrigni T, Nichols CG: Regulation of KATP channel activity by diazoxide and MgADP: distinct functions of the two nucleotide binding folds of the sulfonylurea receptor. J Gen Physiol110 :643 eC654,1997
Shyng SL, Ferrigni T, Shepard JB, Nestorowicz A, Glaser B, Permutt MA, Nichols CG: Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy. Diabetes47 :1145 eC1151,1998
John SA, Weiss JN, Xie LH, Ribalet B: Molecular mechanism for ATP-dependent closure of the K+ channel Kir6.2. J Physiol552 :23 eC34,2003
Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA: Crystal structure of the potassium channel KirBac1.1 in the closed state. Science300 :1922 eC1926,2003
Antcliff JF, Haider S, Proks P, Sansom MS, Ashcroft FM: Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit. EMBO J24 :229 eC239,2005
Shyng SL, Cukras CA, Harwood J, Nichols CG: Structural determinants of PIP(2) regulation of inward rectifier K(ATP) channels. J Gen Physiol116 :599 eC608,2000
Cukras CA, Jeliazkova I, Nichols CG: The role of N-terminal positive charges in the activity of inward rectifier KATP channels. J Gen Physiol120 :437 eC446,2002
Enkvetchakul D, Loussouarn G, Makhina E, Shyng SL, Nichols CG: The kinetic and physical basis of K(ATP) channel gating: toward a unified molecular understanding. Biophys J78 :2334 eC2348,2000
Loussouarn G, Makhina EN, Rose T, Nichols CG: Structure and dynamics of the pore of inwardly rectifying K(ATP) channels. J Biol Chem275 :1137 eC1144,2000
Cartier EA, Shen S, Shyng SL: Modulation of the trafficking efficiency and functional properties of ATP-sensitive potassium channels through a single amino acid in the sulfonylurea receptor. J Biol Chem278 :7081 eC7090,2003
Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptacek LJ: Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell105 :511 eC519,2001
Lopes CM, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE: Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. Neuron34 :933 eC944,2002
Gloyn AL, Hashim Y, Ashcroft SJ, Ashfield R, Wiltshire S, Turner RC, the UK Prospective Diabetes Study (UKPDS 53): Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with type 2 diabetes mellitus (UKPDS 53). Diabet Med18 :206 eC212,2001
Reimann F, Tucker SJ, Proks P, Ashcroft FM: Involvement of the n-terminus of Kir6.2 in coupling to the sulphonylurea receptor. J Physiol (Lond)518 :325 eC336,1999(Joseph C. Koster, M. Alan)