Membrane trafficking and the regulation of NKCC2
http://www.100md.com
《美国生理学杂志》
Renal Division, Brigham and Women's Hospital, and Division of General Internal Medicine, Veterans Affairs Boston Healthcare System, Harvard Medical School, Boston, Massachusetts
THE APICAL NA+-K+-2CL– COTRANSPORTER of the thick ascending limb (TAL; NKCC2) plays a critical role in the countercurrent multiplication mechanism that drives urinary concentration in response to vasopressin (16). The paper by Ortiz (20) in this issue of AJP-Renal Physiology nicely complements prior work on the regulation of NKCC2 by vasopressin and cAMP, highlighting the role of transporter trafficking in the acute response to this hormone.
The NKCC2 protein, also known as BSC-1, is encoded by the SLC12A1 gene, a member of the cation-chloride cotransporter gene family (12). Heterologous expression of NKCC2 in Xenopus laevis oocytes reveals the expected functional characteristics, i.e., diuretic-sensitive cotransport of Na+ (26) and K+ (86Rb+) (7) that is Cl– dependent. Notably, alternative splicing of three cassette exons in SLC12A1 generates isoforms that differ in both distribution along the TAL (13) and in the sequence of transmembrane domain 2 and a flanking intracellular loop (22). These three isoforms differ dramatically in their affinity for the three transported ions (10, 25), leading to novel insights into the mechanism of ion transport by this important transporter (6). NKCC2 is activated about twofold by cell shrinkage, due, at least in part, to phosphorylation of a cluster of NH2-terminal threonines (8) that were initially identified in NKCC1 (SLC12A2) (2), the widely expressed "secretory" Na+-K+-2Cl– cotransporter. Unfortunately, regulatory characterization of NKCC2 is of necessity limited to X. laevis oocytes; attempts by at least two groups have failed repeatedly to express this transporter in mammalian cells, in contrast to the success in expressing other cation-chloride cotransporters in HEK293 cells (21, 23) and Madin-Darby canine kidney cells (29). As a consequence, considerably less is known about the cell biology and posttranscriptional regulation of NKCC2 than that of aquaporin-2 (1) and other key renal transport proteins.
Luminal absorption of Na+-Cl– via NKCC2 conspires with the low water permeability of the TAL and the countercurrent mechanism to increase medullary tonicity, thus facilitating water absorption by the collecting duct. Vasopressin has both long-term and short-term effects on NKCC2 expression and function, resulting in an enhancement of countercurrent multiplication (16). Subjecting rats to moderate water restriction or DDAVP treatment for 7 days thus results in an increase in the expression of NKCC2 (15). Long-term increases in cAMP presumably stimulate NKCC2 expression via a cAMP response element in the SLC12A1 promoter (4, 14). Several hormones other than vasopressin serve to increase cAMP in the TAL; these include parathyroid hormone, glucagon, and calcitonin (3). In contrast, coupling of the calcium-sensing receptor and the EP3 prostaglandin receptor to inhibitory G proteins is thought to reduce cAMP generation in the TAL (27), leading to a reduction in NKCC2 expression (5, 28).
Vasopressin has well-documented acute effects on NKCC2, activating apical Na+-K+-2Cl– cotransport (18) within minutes in perfused TAL (11). Immunoelectron microscopy by Nielsen et al. (19) indicated the expression of NKCC2 protein at the plasma membrane of TAL cells and in abundant subapical vesicles, suggesting a potential role for membrane translocation of the transporter in the acute response to vasopressin/cAMP. More recently, Gimenez and Forbush (9) demonstrated acute phosphorylation of NKCC2 in vivo in response to vasopressin, using a phosphospecific antibody that recognizes the phosphorylated threonines mentioned above (8). This was accompanied by a 55% increase in immunoreactive NKCC2 protein at the apical membrane, as measured by electron microscopy (9). Using surface biotinylation, Ortiz (20) reports that only 2–3% of total NKCC2 protein is at the cell surface of the TAL under basal conditions and that surface-accessible NKCC2 increases by 125 and 95%, respectively, in response to brief incubation with dibutyryl-cAMP or forskolin/IBMX. Notably, tetanus toxin, which blocks vesicle fusion with the plasma membrane by proteolysis of the vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) vesicle-associated membrane proteins (VAMP) -2 and VAMP-3, abrogates the effect of cAMP on NKCC2 expression at the plasma membrane. The VAMP-2 and VAMP-3 proteins were also colocalized with NKCC2 at the apical membrane of rat TAL cells. Finally, Ortiz provides a functional correlate, showing that tetanus toxin abolishes the stimulatory effect of cAMP on net chloride absorption by perfused TAL segments.
This single-author study thus provides biochemical confirmation that cAMP and, by extension, vasopressin, stimulates translocation of NKCC2 to the plasma membrane of the TAL. Furthermore, the data showing inhibition of cAMP-stimulated chloride transport by tetanus toxin provide indirect confirmation of the role of vesicle-dependent trafficking in the acute response to vasopressin. As with all good science, this study highlights a number of further questions. For example, what is the role of other SNARE proteins expressed in the TAL (20) and which of these proteins, if any, directly interact with NKCC2 How does the NH2-terminal phosphorylation of NKCC2 (8), stimulated in vivo by vasopressin (9), affect membrane translocation COOH-terminal splice forms of mouse NKCC2 differ in both functional characteristics (24) and membrane trafficking (17), at least when expressed in X. laevis oocytes; how does this COOH-terminal heterogeneity affect interaction with SNARE proteins and/or membrane trafficking in vivo Bridging the gap between X. laevis oocyte studies and the TAL will be a particular challenge, given the difficulties in expressing NKCC2 in mammalian cells. One hopes, however, that some of the answers will emerge from multidisciplinary studies of the likes of this report.
GRANTS
D. B. Mount is supported by the Department of Veterans Affairs and by National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1-DK-57708.
FOOTNOTES
REFERENCES
Brown D. The ins and outs of aquaporin-2 trafficking. Am J Physiol Renal Physiol 284: F893–F901, 2003.
Darman RB and Forbush B. A regulatory locus of phosphorylation in the N terminus of the Na-K-Cl cotransporter, NKCC1. J Biol Chem 277: 37542–37550, 2002.
De Rouffignac C, Di Stefano A, Wittner M, Roinel N, and Elalouf JM. Consequences of differential effects of ADH and other peptide hormones on thick ascending limb of mammalian kidney. Am J Physiol Regul Integr Comp Physiol 260: R1023–R1035, 1991.
Ecelbarger CA, Yu S, Lee AJ, Weinstein LS, and Knepper MA. Decreased renal Na-K-2Cl cotransporter abundance in mice with heterozygous disruption of the Gs gene. Am J Physiol Renal Physiol 277: F235–F244, 1999.
Fernandez-Llama P, Ecelbarger CA, Ware JA, Andrews P, Lee AJ, Turner R, Nielsen S, and Knepper MA. Cyclooxygenase inhibitors increase Na-K-2Cl cotransporter abundance in thick ascending limb of Henle's loop. Am J Physiol Renal Physiol 277: F219–F226, 1999.
Gagnon E, Bergeron MJ, Daigle ND, Lefoll MH, and Isenring P. Molecular mechanisms of cation transport by the renal Na+-K+-Cl– cotransporter: structural insight into the operating characteristics of the ion transport sites. J Biol Chem 280: 32555–32563, 2005.
Gamba G, Miyanoshita A, Lombardi M, Lytton J, Lee WS, Hediger MA, and Hebert SC. Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney. J Biol Chem 269: 17713–17722, 1994.
Gimenez I and Forbush B. Regulatory phosphorylation sites in the NH2 terminus of the renal Na-K-Cl cotransporter (NKCC2). Am J Physiol Renal Physiol 289: F1341–F1345, 2005.
Gimenez I and Forbush B. Short-term stimulation of the renal Na-K-Cl cotransporter (NKCC2) by vasopressin involves phosphorylation and membrane translocation of the protein. J Biol Chem 278: 26946–26951, 2003.
Gimenez I, Isenring P, and Forbush B. Spatially distributed alternative splice variants of the renal Na-K-Cl cotransporter exhibit dramatically different affinities for the transported ions. J Biol Chem 277: 8767–8770, 2002.
Hebert SC, Culpepper RM, and Andreoli TE. NaCl transport in mouse medullary thick ascending limbs. I. Functional nephron heterogeneity and ADH-stimulated NaCl cotransport. Am J Physiol Renal Fluid Electrolyte Physiol 241: F412–F431, 1981.
Hebert SC, Mount DB, and Gamba G. Molecular physiology of cation-coupled Cl– cotransport: the SLC12 family. Pflügers Arch 447: 580–593, 2004.
Igarashi P, Vanden Heuvel GB, Payne JA, and Forbush B III. Cloning, embryonic expression, and alternative splicing of a murine kidney-specific Na-K-Cl cotransporter. Am J Physiol Renal Fluid Electrolyte Physiol 269: F405–F418, 1995.
Igarashi P, Whyte DA, Li K, and Nagami GT. Cloning and kidney cell-specific activity of the promoter of the murine renal Na-K-C1 cotransporter gene. J Biol Chem 271: 9666–9674, 1996.
Kim GH, Ecelbarger CA, Mitchell C, Packer RK, Wade JB, and Knepper MA. Vasopressin increases Na-K-2Cl cotransporter expression in thick ascending limb of Henle's loop. Am J Physiol Renal Physiol 276: F96–F103, 1999.
Knepper MA, Kim GH, Fernandez-Llama P, and Ecelbarger CA. Regulation of thick ascending limb transport by vasopressin. J Am Soc Nephrol 10: 628–634, 1999.
Meade P, Hoover RS, Plata C, Vazquez N, Bobadilla NA, Gamba G, and Hebert SC. cAMP-dependent activation of the renal-specific Na+-K+-2Cl– cotransporter is mediated by regulation of cotransporter trafficking. Am J Physiol Renal Physiol 284: F1145–F1154, 2003.
Molony DA, Reeves WB, Hebert SC, and Andreoli TE. ADH increases apical Na+, K+, 2Cl– entry in mouse medullary thick ascending limbs of Henle. Am J Physiol Renal Fluid Electrolyte Physiol 252: F177–F187, 1987.
Nielsen S, Maunsbach AB, Ecelbarger CA, and Knepper MA. Ultrastructural localization of Na-K-2Cl cotransporter in thick ascending limb and macula densa of rat kidney. Am J Physiol Renal Physiol 275: F885–F893, 1998.
Ortiz PA. cAMP increases surface expression of NKCC2 in rat thick ascending limbs: role of VAMP. Am J Physiol Renal Physiol 290: F608–F616, 2006.
Payne JA. Functional characterization of the neuronal-specific K-Cl cotransporter: implications for [K+]o regulation. Am J Physiol Cell Physiol 273: C1516–C1525, 1997.
Payne JA and Forbush B III. Alternatively spliced isoforms of the putative renal Na-K-Cl cotransporter are differentially distributed within the rabbit kidney. Proc Natl Acad Sci USA 91: 4544–4548, 1994.
Payne JA, Xu JC, Haas M, Lytle CY, Ward D, and Forbush B III. Primary structure, functional expression, and chromosomal localization of the bumetanide-sensitive Na-K-Cl cotransporter in human colon. J Biol Chem 270: 17977–17985, 1995.
Plata C, Meade P, Hall A, Welch RC, Vazquez N, Hebert SC, and Gamba G. Alternatively spliced isoform of apical Na+-K+-Cl– cotransporter gene encodes a furosemide-sensitive Na+-Cl– cotransporter. Am J Physiol Renal Physiol 280: F574–F582, 2001.
Plata C, Meade P, Vazquez N, Hebert SC, and Gamba G. Functional properties of the apical Na+-K+-2Cl– cotransporter isoforms. J Biol Chem 277: 11004–11012, 2002.
Plata C, Mount DB, Rubio V, Hebert SC, and Gamba G. Isoforms of the apical Na-K-2Cl transporter in murine TAL. II. Functional characterization and mechanism of activation by cAMP. Am J Physiol Renal Physiol 276: F359–F366, 1999.
Takaichi K and Kurokawa K. Inhibitory guanosine triphosphate-binding protein-mediated regulation of vasopressin action in isolated single medullary tubules of mouse kidney. J Clin Invest 82: 1437–1444, 1988.
Wang W, Kwon TH, Li C, Frkir J, Knepper MA, and Nielsen S. Reduced expression of Na-K-2Cl cotransporter in medullary TAL in vitamin D-induced hypercalcemia in rats. Am J Physiol Renal Physiol 282: F34–F44, 2002.
Williams JR and Payne JA. Cation transport by the neuronal K+-Cl– cotransporter KCC2: thermodynamics and kinetics of alternate transport modes. Am J Physiol Cell Physiol 287: C919–C931, 2004.(David B. Mount)
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The NKCC2 protein, also known as BSC-1, is encoded by the SLC12A1 gene, a member of the cation-chloride cotransporter gene family (12). Heterologous expression of NKCC2 in Xenopus laevis oocytes reveals the expected functional characteristics, i.e., diuretic-sensitive cotransport of Na+ (26) and K+ (86Rb+) (7) that is Cl– dependent. Notably, alternative splicing of three cassette exons in SLC12A1 generates isoforms that differ in both distribution along the TAL (13) and in the sequence of transmembrane domain 2 and a flanking intracellular loop (22). These three isoforms differ dramatically in their affinity for the three transported ions (10, 25), leading to novel insights into the mechanism of ion transport by this important transporter (6). NKCC2 is activated about twofold by cell shrinkage, due, at least in part, to phosphorylation of a cluster of NH2-terminal threonines (8) that were initially identified in NKCC1 (SLC12A2) (2), the widely expressed "secretory" Na+-K+-2Cl– cotransporter. Unfortunately, regulatory characterization of NKCC2 is of necessity limited to X. laevis oocytes; attempts by at least two groups have failed repeatedly to express this transporter in mammalian cells, in contrast to the success in expressing other cation-chloride cotransporters in HEK293 cells (21, 23) and Madin-Darby canine kidney cells (29). As a consequence, considerably less is known about the cell biology and posttranscriptional regulation of NKCC2 than that of aquaporin-2 (1) and other key renal transport proteins.
Luminal absorption of Na+-Cl– via NKCC2 conspires with the low water permeability of the TAL and the countercurrent mechanism to increase medullary tonicity, thus facilitating water absorption by the collecting duct. Vasopressin has both long-term and short-term effects on NKCC2 expression and function, resulting in an enhancement of countercurrent multiplication (16). Subjecting rats to moderate water restriction or DDAVP treatment for 7 days thus results in an increase in the expression of NKCC2 (15). Long-term increases in cAMP presumably stimulate NKCC2 expression via a cAMP response element in the SLC12A1 promoter (4, 14). Several hormones other than vasopressin serve to increase cAMP in the TAL; these include parathyroid hormone, glucagon, and calcitonin (3). In contrast, coupling of the calcium-sensing receptor and the EP3 prostaglandin receptor to inhibitory G proteins is thought to reduce cAMP generation in the TAL (27), leading to a reduction in NKCC2 expression (5, 28).
Vasopressin has well-documented acute effects on NKCC2, activating apical Na+-K+-2Cl– cotransport (18) within minutes in perfused TAL (11). Immunoelectron microscopy by Nielsen et al. (19) indicated the expression of NKCC2 protein at the plasma membrane of TAL cells and in abundant subapical vesicles, suggesting a potential role for membrane translocation of the transporter in the acute response to vasopressin/cAMP. More recently, Gimenez and Forbush (9) demonstrated acute phosphorylation of NKCC2 in vivo in response to vasopressin, using a phosphospecific antibody that recognizes the phosphorylated threonines mentioned above (8). This was accompanied by a 55% increase in immunoreactive NKCC2 protein at the apical membrane, as measured by electron microscopy (9). Using surface biotinylation, Ortiz (20) reports that only 2–3% of total NKCC2 protein is at the cell surface of the TAL under basal conditions and that surface-accessible NKCC2 increases by 125 and 95%, respectively, in response to brief incubation with dibutyryl-cAMP or forskolin/IBMX. Notably, tetanus toxin, which blocks vesicle fusion with the plasma membrane by proteolysis of the vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) vesicle-associated membrane proteins (VAMP) -2 and VAMP-3, abrogates the effect of cAMP on NKCC2 expression at the plasma membrane. The VAMP-2 and VAMP-3 proteins were also colocalized with NKCC2 at the apical membrane of rat TAL cells. Finally, Ortiz provides a functional correlate, showing that tetanus toxin abolishes the stimulatory effect of cAMP on net chloride absorption by perfused TAL segments.
This single-author study thus provides biochemical confirmation that cAMP and, by extension, vasopressin, stimulates translocation of NKCC2 to the plasma membrane of the TAL. Furthermore, the data showing inhibition of cAMP-stimulated chloride transport by tetanus toxin provide indirect confirmation of the role of vesicle-dependent trafficking in the acute response to vasopressin. As with all good science, this study highlights a number of further questions. For example, what is the role of other SNARE proteins expressed in the TAL (20) and which of these proteins, if any, directly interact with NKCC2 How does the NH2-terminal phosphorylation of NKCC2 (8), stimulated in vivo by vasopressin (9), affect membrane translocation COOH-terminal splice forms of mouse NKCC2 differ in both functional characteristics (24) and membrane trafficking (17), at least when expressed in X. laevis oocytes; how does this COOH-terminal heterogeneity affect interaction with SNARE proteins and/or membrane trafficking in vivo Bridging the gap between X. laevis oocyte studies and the TAL will be a particular challenge, given the difficulties in expressing NKCC2 in mammalian cells. One hopes, however, that some of the answers will emerge from multidisciplinary studies of the likes of this report.
GRANTS
D. B. Mount is supported by the Department of Veterans Affairs and by National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1-DK-57708.
FOOTNOTES
REFERENCES
Brown D. The ins and outs of aquaporin-2 trafficking. Am J Physiol Renal Physiol 284: F893–F901, 2003.
Darman RB and Forbush B. A regulatory locus of phosphorylation in the N terminus of the Na-K-Cl cotransporter, NKCC1. J Biol Chem 277: 37542–37550, 2002.
De Rouffignac C, Di Stefano A, Wittner M, Roinel N, and Elalouf JM. Consequences of differential effects of ADH and other peptide hormones on thick ascending limb of mammalian kidney. Am J Physiol Regul Integr Comp Physiol 260: R1023–R1035, 1991.
Ecelbarger CA, Yu S, Lee AJ, Weinstein LS, and Knepper MA. Decreased renal Na-K-2Cl cotransporter abundance in mice with heterozygous disruption of the Gs gene. Am J Physiol Renal Physiol 277: F235–F244, 1999.
Fernandez-Llama P, Ecelbarger CA, Ware JA, Andrews P, Lee AJ, Turner R, Nielsen S, and Knepper MA. Cyclooxygenase inhibitors increase Na-K-2Cl cotransporter abundance in thick ascending limb of Henle's loop. Am J Physiol Renal Physiol 277: F219–F226, 1999.
Gagnon E, Bergeron MJ, Daigle ND, Lefoll MH, and Isenring P. Molecular mechanisms of cation transport by the renal Na+-K+-Cl– cotransporter: structural insight into the operating characteristics of the ion transport sites. J Biol Chem 280: 32555–32563, 2005.
Gamba G, Miyanoshita A, Lombardi M, Lytton J, Lee WS, Hediger MA, and Hebert SC. Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney. J Biol Chem 269: 17713–17722, 1994.
Gimenez I and Forbush B. Regulatory phosphorylation sites in the NH2 terminus of the renal Na-K-Cl cotransporter (NKCC2). Am J Physiol Renal Physiol 289: F1341–F1345, 2005.
Gimenez I and Forbush B. Short-term stimulation of the renal Na-K-Cl cotransporter (NKCC2) by vasopressin involves phosphorylation and membrane translocation of the protein. J Biol Chem 278: 26946–26951, 2003.
Gimenez I, Isenring P, and Forbush B. Spatially distributed alternative splice variants of the renal Na-K-Cl cotransporter exhibit dramatically different affinities for the transported ions. J Biol Chem 277: 8767–8770, 2002.
Hebert SC, Culpepper RM, and Andreoli TE. NaCl transport in mouse medullary thick ascending limbs. I. Functional nephron heterogeneity and ADH-stimulated NaCl cotransport. Am J Physiol Renal Fluid Electrolyte Physiol 241: F412–F431, 1981.
Hebert SC, Mount DB, and Gamba G. Molecular physiology of cation-coupled Cl– cotransport: the SLC12 family. Pflügers Arch 447: 580–593, 2004.
Igarashi P, Vanden Heuvel GB, Payne JA, and Forbush B III. Cloning, embryonic expression, and alternative splicing of a murine kidney-specific Na-K-Cl cotransporter. Am J Physiol Renal Fluid Electrolyte Physiol 269: F405–F418, 1995.
Igarashi P, Whyte DA, Li K, and Nagami GT. Cloning and kidney cell-specific activity of the promoter of the murine renal Na-K-C1 cotransporter gene. J Biol Chem 271: 9666–9674, 1996.
Kim GH, Ecelbarger CA, Mitchell C, Packer RK, Wade JB, and Knepper MA. Vasopressin increases Na-K-2Cl cotransporter expression in thick ascending limb of Henle's loop. Am J Physiol Renal Physiol 276: F96–F103, 1999.
Knepper MA, Kim GH, Fernandez-Llama P, and Ecelbarger CA. Regulation of thick ascending limb transport by vasopressin. J Am Soc Nephrol 10: 628–634, 1999.
Meade P, Hoover RS, Plata C, Vazquez N, Bobadilla NA, Gamba G, and Hebert SC. cAMP-dependent activation of the renal-specific Na+-K+-2Cl– cotransporter is mediated by regulation of cotransporter trafficking. Am J Physiol Renal Physiol 284: F1145–F1154, 2003.
Molony DA, Reeves WB, Hebert SC, and Andreoli TE. ADH increases apical Na+, K+, 2Cl– entry in mouse medullary thick ascending limbs of Henle. Am J Physiol Renal Fluid Electrolyte Physiol 252: F177–F187, 1987.
Nielsen S, Maunsbach AB, Ecelbarger CA, and Knepper MA. Ultrastructural localization of Na-K-2Cl cotransporter in thick ascending limb and macula densa of rat kidney. Am J Physiol Renal Physiol 275: F885–F893, 1998.
Ortiz PA. cAMP increases surface expression of NKCC2 in rat thick ascending limbs: role of VAMP. Am J Physiol Renal Physiol 290: F608–F616, 2006.
Payne JA. Functional characterization of the neuronal-specific K-Cl cotransporter: implications for [K+]o regulation. Am J Physiol Cell Physiol 273: C1516–C1525, 1997.
Payne JA and Forbush B III. Alternatively spliced isoforms of the putative renal Na-K-Cl cotransporter are differentially distributed within the rabbit kidney. Proc Natl Acad Sci USA 91: 4544–4548, 1994.
Payne JA, Xu JC, Haas M, Lytle CY, Ward D, and Forbush B III. Primary structure, functional expression, and chromosomal localization of the bumetanide-sensitive Na-K-Cl cotransporter in human colon. J Biol Chem 270: 17977–17985, 1995.
Plata C, Meade P, Hall A, Welch RC, Vazquez N, Hebert SC, and Gamba G. Alternatively spliced isoform of apical Na+-K+-Cl– cotransporter gene encodes a furosemide-sensitive Na+-Cl– cotransporter. Am J Physiol Renal Physiol 280: F574–F582, 2001.
Plata C, Meade P, Vazquez N, Hebert SC, and Gamba G. Functional properties of the apical Na+-K+-2Cl– cotransporter isoforms. J Biol Chem 277: 11004–11012, 2002.
Plata C, Mount DB, Rubio V, Hebert SC, and Gamba G. Isoforms of the apical Na-K-2Cl transporter in murine TAL. II. Functional characterization and mechanism of activation by cAMP. Am J Physiol Renal Physiol 276: F359–F366, 1999.
Takaichi K and Kurokawa K. Inhibitory guanosine triphosphate-binding protein-mediated regulation of vasopressin action in isolated single medullary tubules of mouse kidney. J Clin Invest 82: 1437–1444, 1988.
Wang W, Kwon TH, Li C, Frkir J, Knepper MA, and Nielsen S. Reduced expression of Na-K-2Cl cotransporter in medullary TAL in vitamin D-induced hypercalcemia in rats. Am J Physiol Renal Physiol 282: F34–F44, 2002.
Williams JR and Payne JA. Cation transport by the neuronal K+-Cl– cotransporter KCC2: thermodynamics and kinetics of alternate transport modes. Am J Physiol Cell Physiol 287: C919–C931, 2004.(David B. Mount)
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