Distinct Regulatory Effects of the Na,K-ATPase γ Subunit

The two variants of the γ subunit of the rat renal sodium pump, γa and γb, have similar effects on the Na,K-ATPase. Both increase the affinity for ATP due to a shift in the enzyme's E1 ↔ E2 conformational equilibrium toward E1. In addition, both increase K+ antagonism of cytoplasmic Na+ activation. To gain insight into the structural basis for these distinct effects, extramembranous N-terminal and C-terminal mutants of γ were expressed in rat α1-transfected HeLa cells. At the N terminus, the variant-distinct region was deleted (γNΔ7) or replaced by alanine residues (γN7A). At the C terminus, four (γaCΔ4) or ten (γaCΔ10) residues were deleted. None of these mutations abrogates the K+/Na+ antagonism as evidenced in a similar increase in K′Na seen at high (100 mm) K+ concentration. In contrast, the C-terminal as well as N-terminal deletions (γNΔ7, γaCΔ4, and γaCΔ10) abolished the decrease in K′ATP seen with wild-type γa or γb. It is concluded that different regions of the γ chain mediate the distinct functional effects of γ, and the effects can be long-range. In the transmembrane region, the impact of G41R replacement was analyzed since this mutation is associated with autosomal dominant renal Mg2+-wasting in man (Meij, I. C., Koenderink, J. B., van Bokhoven, H., Assink, K. F. H., Groenestege, W. T., de Pont, J. J. H. H. M., Bindels, R. J. M., Monnens, L. A. H., Van den Heuvel, L. P. W. J., and Knoers, N. V. A. M. (2000) Nat. Genet. 26, 265–266). The results show that Gly-41 → Arg prevents trafficking of γ but not αβ pumps to the cell surface and abrogates functional effects of γ on αβ pumps. These findings underscore a potentially important role of γ in affecting solute transport, in this instance Mg2+ reabsorption, consequent to its primary effect on the sodium pump. The two variants of the γ subunit of the rat renal sodium pump, γa and γb, have similar effects on the Na,K-ATPase. Both increase the affinity for ATP due to a shift in the enzyme's E1 ↔ E2 conformational equilibrium toward E1. In addition, both increase K+ antagonism of cytoplasmic Na+ activation. To gain insight into the structural basis for these distinct effects, extramembranous N-terminal and C-terminal mutants of γ were expressed in rat α1-transfected HeLa cells. At the N terminus, the variant-distinct region was deleted (γNΔ7) or replaced by alanine residues (γN7A). At the C terminus, four (γaCΔ4) or ten (γaCΔ10) residues were deleted. None of these mutations abrogates the K+/Na+ antagonism as evidenced in a similar increase in K′Na seen at high (100 mm) K+ concentration. In contrast, the C-terminal as well as N-terminal deletions (γNΔ7, γaCΔ4, and γaCΔ10) abolished the decrease in K′ATP seen with wild-type γa or γb. It is concluded that different regions of the γ chain mediate the distinct functional effects of γ, and the effects can be long-range. In the transmembrane region, the impact of G41R replacement was analyzed since this mutation is associated with autosomal dominant renal Mg2+-wasting in man (Meij, I. C., Koenderink, J. B., van Bokhoven, H., Assink, K. F. H., Groenestege, W. T., de Pont, J. J. H. H. M., Bindels, R. J. M., Monnens, L. A. H., Van den Heuvel, L. P. W. J., and Knoers, N. V. A. M. (2000) Nat. Genet. 26, 265–266). The results show that Gly-41 → Arg prevents trafficking of γ but not αβ pumps to the cell surface and abrogates functional effects of γ on αβ pumps. These findings underscore a potentially important role of γ in affecting solute transport, in this instance Mg2+ reabsorption, consequent to its primary effect on the sodium pump. The Na,K-ATPase, or sodium pump, maintains the high Na+ and K+ gradients across the plasma membrane of animal cells. Accordingly, this pump plays a major role in determining the cytoplasmic Na+ concentration and hence the cytoplasmic concentration of protons and Ca2+, as well as other solutes whose accumulation is driven by secondary countertransport systems. The kinetic properties of the sodium pump are, in turn, subject to complex mechanisms of short- and long-term regulation. While the nature of the catalytic α subunit isoform may be a primary determinant of tissue-specific behavior of the pump, there are also diverse mechanisms underlying pump regulation. (For review, see Refs. 1Feraille E. Doucet A. Physiol. Rev. 2001; 81: 345-418Crossref PubMed Scopus (424) Google Scholar and 2Therien A.G. Blostein R. Amer. J. Physiol. Cell Physiol. 2000; 279: C541-C566Crossref PubMed Google Scholar).There is an increasing body of evidence that a family of small, single transmembrane proteins characterized by the motif FXYD are expressed in a tissue-specific manner. To date, at least two members have been identified in kidney, FXYD2 or γ (4Mercer R.W. Biemesderfer D. Bliss D.P., Jr. Collins J.H. Forbush III B. J. Cell Biol. 1993; 121: 579-586Crossref PubMed Scopus (184) Google Scholar, 5Therien A.G. Goldshleger R. Karlish S.J.D. R. B. J. Biol. Chem. 1997; 272: 32628-32634Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) and FXYD4 or the corticosteroid hormone-induced factor, CHIF 1The abbreviations used are: CHIFcorticosteroid hormone-induced factorPFOperfluorooctanoatePRMplasma-rich membranesHDMhigh density microsomal membranesLDMlow density membranesMES4-morpholineethanesulfonic acidWTwild-typeNHSN-hydroxysuccinimide1The abbreviations used are: CHIFcorticosteroid hormone-induced factorPFOperfluorooctanoatePRMplasma-rich membranesHDMhigh density microsomal membranesLDMlow density membranesMES4-morpholineethanesulfonic acidWTwild-typeNHSN-hydroxysuccinimide (6Attali B. Latter H. Rachamim N. Garty H. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 6092-6096Crossref PubMed Scopus (176) Google Scholar, 7Capurro C. Coutry N. Bonvalet J.P. Escoubet B. Garty H. N. Amer. J. Physiol. Physiol. PubMed Google Scholar, H. R. F. N. Garty H. Amer. J. Physiol. Physiol. 2001; PubMed Google Both the kinetic behavior of the Refs. 5Therien A.G. Goldshleger R. Karlish S.J.D. R. B. J. Biol. Chem. 1997; 272: 32628-32634Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, P. D. A. D. J. 1997; PubMed Scopus Google Scholar, A.G. Karlish S.J.D. Blostein R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, P. S. Garty H. K. J. 2001; PubMed Scopus Google Scholar for γ and for of H. F. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google to in J. Biol. Chem. Full Text PDF PubMed Google also in a manner. To date, at least members of this family have been identified K. E. 2001; Scopus Google γ subunit of the was B. J.H. PubMed Scopus Google Scholar, J.H. J. PubMed Scopus Google Scholar) and was to as two major variants in the kidney, γa and B. A. M. Blostein R. Goldshleger R. Karlish S.J.D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google with on the E. 2000; 279: PubMed Scopus Google These are variants and in N-terminal In the the N-terminal of γa are replaced by in B. A. M. Blostein R. Goldshleger R. Karlish S.J.D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google in that a may be Physiol. 2001; PubMed Scopus Google have and expressed the γa and variants in and characterized two A.G. Karlish S.J.D. Blostein R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar and F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar and in A.G. Karlish S.J.D. Blostein R. J. 2001; PubMed Scopus Google of γ is to increase cytoplasmic of Na+ is as an increase in at K+ The other is a increase in the affinity for with that the C of γ the affinity for ATP A.G. Goldshleger R. Karlish S.J.D. R. B. J. Biol. Chem. 1997; 272: 32628-32634Abstract Full Text Full Text PDF PubMed Scopus (125) Google the decrease in K′ATP to a shift in the of the E1 ↔ E2 equilibrium toward E1. with this is the behavior of both γ expressed in P. S. Garty H. K. J. 2001; PubMed Scopus Google in the but not of both the affinity for K+ in a membrane of a shift in conformational equilibrium toward E1. γa and be F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google the of the of two major variants of γ may be to but distinct of F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, Amer. J. Physiol. Physiol. 2001; PubMed Google in turn, may be to the of this was to gain insight into the structural basis for the two distinct effects of To this the of both and C-terminal extramembranous regions of γ by and alanine replacement of the N and of to ten residues the C The other was to the functional basis for the transmembrane Gly-41 → Arg mutation associated with in man van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google an important role of γ in affecting secondary as a of primary effects on γ subunit of the sodium pump is a of the FXYD family of transmembrane are at least members of this family in K. E. 2001; Scopus Google In the kidney, two CHIF and γ, are of the pump with effects on affinity for Na+ P. S. Garty H. K. J. 2001; PubMed Scopus Google Scholar, H., M., M., M., and S. J. D. Amer. J. Physiol. in that the is CHIF is in and and γ in the H. F. N. Goldshleger R. Karlish S.J.D. J. 2001; The two major γ variants have not functional effects on the sodium pump the other there are in the both to of the and are in the of Na+ are also distinct F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) that but not γa was in γa is in the region of the in is by and Amer. J. Physiol. Physiol. 2001; PubMed Google Scholar) have that is in the and is functional effects of γ the an increase in affinity for ATP a shift in the toward the E1 and an increase in K+/Na+ at cytoplasmic Na+ these effects in of the in ↔ E1 K+ and E1 ATP Na+ ↔ is that the two effects of γ are affinity for K+ at cytoplasmic Na+ shift the E1 a affinity for ATP shift the toward E1. The of these are that of the renal the effect of γ on K′ATP but effect on K+/Na+ that the two effects of γ are to different regions of the γ The evidence in of this of ten and as as four residues the C terminus, as well as of the N terminus, abrogates the decrease in K′ATP seen with both variants but not the increase in K+/Na+ is that there is the two effects of γ the increase in K′ATP affinity may and hence the K+/Na+ antagonism and may γ effects on behavior are, in turn, by of with other cell as of the that of the extramembranous mutants both effects of γ that of these γ with is with the of P. S. Garty H. K. J. 2001; PubMed Scopus Google that the FXYD motif that is in these mutants is for that of the N terminus, of the C of abrogates the effect of γ on the E1 ↔ E2 conformational equilibrium to effects of on the N-terminal but not replacement abrogates the K′ATP the γ effect to E1 not or with αβ but the of the γ basis for the effects of γ is that a for and gradients across renal cells. Both γ variants are in the A.G. Karlish S.J.D. Blostein R. J. 2001; PubMed Scopus Google is in the regions of the that the affinity for ATP by γ to pump and the decrease in Na+ affinity to ATP and an Accordingly, its effect γ to the pump with the to ATP and be by an increase in the Na+ concentration by Garty H. F. N. Goldshleger R. Karlish S.J.D. J. 2001; Scholar) have that in regions with γ in the affinity for Na+ is C. L. S. C. Doucet A. J. Physiol. Physiol. PubMed Google in and the renal pump is associated with CHIF the effect of γ on K′Na P. S. Garty H. K. J. 2001; PubMed Scopus Google the affinity for Na+ at least these may be for have an important role in Na+ and K+ It is not in to the γ the increase in Na+ affinity by CHIF a decrease in the affinity for K+ as a of cytoplasmic Na+ important role of γ in renal secondary to its and is by results the functional of Gly-41 to evidence that the G41R γ with the αβ pump, in the of γ both to to the cell surface and to pump The the γ by van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google In addition, that αβ pump trafficking is not of the of renal Mg2+-wasting with of γ of is It is that the of in and the different regions of the are and ATP affinity of αβ pumps by of by γ may decrease pump and to secondary in Mg2+ Accordingly, renal Mg2+-wasting seen in the dominant by van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google Scholar) to be secondary to the of γ of The primary to be is the increase in renal and that is in these van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google in this were with cells. The to γ trafficking and of the γ effects by G41R replacement are different in to be are to this of γ in renal cells. The Na,K-ATPase, or sodium pump, maintains the high Na+ and K+ gradients across the plasma membrane of animal cells. Accordingly, this pump plays a major role in determining the cytoplasmic Na+ concentration and hence the cytoplasmic concentration of protons and Ca2+, as well as other solutes whose accumulation is driven by secondary countertransport systems. The kinetic properties of the sodium pump are, in turn, subject to complex mechanisms of short- and long-term regulation. While the nature of the catalytic α subunit isoform may be a primary determinant of tissue-specific behavior of the pump, there are also diverse mechanisms underlying pump regulation. (For review, see Refs. 1Feraille E. Doucet A. Physiol. Rev. 2001; 81: 345-418Crossref PubMed Scopus (424) Google Scholar and 2Therien A.G. Blostein R. Amer. J. Physiol. Cell Physiol. 2000; 279: C541-C566Crossref PubMed Google is an increasing body of evidence that a family of small, single transmembrane proteins characterized by the motif FXYD are expressed in a tissue-specific manner. To date, at least two members have been identified in kidney, FXYD2 or γ (4Mercer R.W. Biemesderfer D. Bliss D.P., Jr. Collins J.H. Forbush III B. J. Cell Biol. 1993; 121: 579-586Crossref PubMed Scopus (184) Google Scholar, 5Therien A.G. Goldshleger R. Karlish S.J.D. R. B. J. Biol. Chem. 1997; 272: 32628-32634Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) and FXYD4 or the corticosteroid hormone-induced factor, CHIF 1The abbreviations used are: CHIFcorticosteroid hormone-induced factorPFOperfluorooctanoatePRMplasma-rich membranesHDMhigh density microsomal membranesLDMlow density membranesMES4-morpholineethanesulfonic acidWTwild-typeNHSN-hydroxysuccinimide1The abbreviations used are: CHIFcorticosteroid hormone-induced factorPFOperfluorooctanoatePRMplasma-rich membranesHDMhigh density microsomal membranesLDMlow density membranesMES4-morpholineethanesulfonic acidWTwild-typeNHSN-hydroxysuccinimide (6Attali B. Latter H. Rachamim N. Garty H. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 6092-6096Crossref PubMed Scopus (176) Google Scholar, 7Capurro C. Coutry N. Bonvalet J.P. Escoubet B. Garty H. N. Amer. J. Physiol. Physiol. PubMed Google Scholar, H. R. F. N. Garty H. Amer. J. Physiol. Physiol. 2001; PubMed Google Both the kinetic behavior of the Refs. 5Therien A.G. Goldshleger R. Karlish S.J.D. R. B. J. Biol. Chem. 1997; 272: 32628-32634Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, P. D. A. D. J. 1997; PubMed Scopus Google Scholar, A.G. Karlish S.J.D. Blostein R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, P. S. Garty H. K. J. 2001; PubMed Scopus Google Scholar for γ and for of H. F. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google to in J. Biol. Chem. Full Text PDF PubMed Google also in a manner. To date, at least members of this family have been identified K. E. 2001; Scopus Google corticosteroid hormone-induced high density microsomal density wild-type corticosteroid hormone-induced high density microsomal density wild-type The γ subunit of the was B. J.H. PubMed Scopus Google Scholar, J.H. J. PubMed Scopus Google Scholar) and was to as two major variants in the kidney, γa and B. A. M. Blostein R. Goldshleger R. Karlish S.J.D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google with on the E. 2000; 279: PubMed Scopus Google These are variants and in N-terminal In the the N-terminal of γa are replaced by in B. A. M. Blostein R. Goldshleger R. Karlish S.J.D. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google in that a may be Physiol. 2001; PubMed Scopus Google have and expressed the γa and variants in and characterized two A.G. Karlish S.J.D. Blostein R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar and F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar and in A.G. Karlish S.J.D. Blostein R. J. 2001; PubMed Scopus Google of γ is to increase cytoplasmic of Na+ is as an increase in at K+ The other is a increase in the affinity for with that the C of γ the affinity for ATP A.G. Goldshleger R. Karlish S.J.D. R. B. J. Biol. Chem. 1997; 272: 32628-32634Abstract Full Text Full Text PDF PubMed Scopus (125) Google the decrease in K′ATP to a shift in the of the E1 ↔ E2 equilibrium toward E1. with this is the behavior of both γ expressed in P. S. Garty H. K. J. 2001; PubMed Scopus Google in the but not of both the affinity for K+ in a membrane of a shift in conformational equilibrium toward E1. γa and be F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google the of the of two major variants of γ may be to but distinct of F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, Amer. J. Physiol. Physiol. 2001; PubMed Google in turn, may be to the of this was to gain insight into the structural basis for the two distinct effects of To this the of both and C-terminal extramembranous regions of γ by and alanine replacement of the N and of to ten residues the C The other was to the functional basis for the transmembrane Gly-41 → Arg mutation associated with in man van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google an important role of γ in affecting secondary as a of primary effects on γ subunit of the sodium pump is a of the FXYD family of transmembrane are at least members of this family in K. E. 2001; Scopus Google In the kidney, two CHIF and γ, are of the pump with effects on affinity for Na+ P. S. Garty H. K. J. 2001; PubMed Scopus Google Scholar, H., M., M., M., and S. J. D. Amer. J. Physiol. in that the is CHIF is in and and γ in the H. F. N. Goldshleger R. Karlish S.J.D. J. 2001; The two major γ variants have not functional effects on the sodium pump the other there are in the both to of the and are in the of Na+ are also distinct F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) that but not γa was in γa is in the region of the in is by and Amer. J. Physiol. Physiol. 2001; PubMed Google Scholar) have that is in the and is functional effects of γ the an increase in affinity for ATP a shift in the toward the E1 and an increase in K+/Na+ at cytoplasmic Na+ these effects in of the in ↔ E1 K+ and E1 ATP Na+ ↔ is that the two effects of γ are affinity for K+ at cytoplasmic Na+ shift the E1 a affinity for ATP shift the toward E1. The of these are that of the renal the effect of γ on K′ATP but effect on K+/Na+ that the two effects of γ are to different regions of the γ The evidence in of this of ten and as as four residues the C terminus, as well as of the N terminus, abrogates the decrease in K′ATP seen with both variants but not the increase in K+/Na+ is that there is the two effects of γ the increase in K′ATP affinity may and hence the K+/Na+ antagonism and may γ effects on behavior are, in turn, by of with other cell as of the that of the extramembranous mutants both effects of γ that of these γ with is with the of P. S. Garty H. K. J. 2001; PubMed Scopus Google that the FXYD motif that is in these mutants is for that of the N terminus, of the C of abrogates the effect of γ on the E1 ↔ E2 conformational equilibrium to effects of on the N-terminal but not replacement abrogates the K′ATP the γ effect to E1 not or with αβ but the of the γ basis for the effects of γ is that a for and gradients across renal cells. Both γ variants are in the A.G. Karlish S.J.D. Blostein R. J. 2001; PubMed Scopus Google is in the regions of the that the affinity for ATP by γ to pump and the decrease in Na+ affinity to ATP and an Accordingly, its effect γ to the pump with the to ATP and be by an increase in the Na+ concentration by Garty H. F. N. Goldshleger R. Karlish S.J.D. J. 2001; Scholar) have that in regions with γ in the affinity for Na+ is C. L. S. C. Doucet A. J. Physiol. Physiol. PubMed Google in and the renal pump is associated with CHIF the effect of γ on K′Na P. S. Garty H. K. J. 2001; PubMed Scopus Google the affinity for Na+ at least these may be for have an important role in Na+ and K+ It is not in to the γ the increase in Na+ affinity by CHIF a decrease in the affinity for K+ as a of cytoplasmic Na+ important role of γ in renal secondary to its and is by results the functional of Gly-41 to evidence that the G41R γ with the αβ pump, in the of γ both to to the cell surface and to pump The the γ by van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google In addition, that αβ pump trafficking is not of the of renal Mg2+-wasting with of γ of is It is that the of in and the different regions of the are and ATP affinity of αβ pumps by of by γ may decrease pump and to secondary in Mg2+ Accordingly, renal Mg2+-wasting seen in the dominant by van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google Scholar) to be secondary to the of γ of The primary to be is the increase in renal and that is in these van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google in this were with cells. The to γ trafficking and of the γ effects by G41R replacement are different in to be are to this of γ in renal cells. The γ subunit of the sodium pump is a of the FXYD family of transmembrane are at least members of this family in K. E. 2001; Scopus Google In the kidney, two CHIF and γ, are of the pump with effects on affinity for Na+ P. S. Garty H. K. J. 2001; PubMed Scopus Google Scholar, H., M., M., M., and S. J. D. Amer. J. Physiol. in that the is CHIF is in and and γ in the H. F. N. Goldshleger R. Karlish S.J.D. J. 2001; The two major γ variants have not functional effects on the sodium pump the other there are in the both to of the and are in the of Na+ are also distinct F. Goldshleger R. Karlish S.J.D. N. Blostein R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) that but not γa was in γa is in the region of the in is by and Amer. J. Physiol. Physiol. 2001; PubMed Google Scholar) have that is in the and is The functional effects of γ the an increase in affinity for ATP a shift in the toward the E1 and an increase in K+/Na+ at cytoplasmic Na+ these effects in of the in ↔ E1 K+ and E1 ATP Na+ ↔ is that the two effects of γ are affinity for K+ at cytoplasmic Na+ shift the E1 a affinity for ATP shift the toward E1. The of these are that of the renal the effect of γ on K′ATP but effect on K+/Na+ that the two effects of γ are to different regions of the γ The evidence in of this of ten and as as four residues the C terminus, as well as of the N terminus, abrogates the decrease in K′ATP seen with both variants but not the increase in K+/Na+ is that there is the two effects of γ the increase in K′ATP affinity may and hence the K+/Na+ antagonism and may γ effects on behavior are, in turn, by of with other cell as of the The that of the extramembranous mutants both effects of γ that of these γ with is with the of P. S. Garty H. K. J. 2001; PubMed Scopus Google that the FXYD motif that is in these mutants is for The that of the N terminus, of the C of abrogates the effect of γ on the E1 ↔ E2 conformational equilibrium to effects of on the N-terminal but not replacement abrogates the K′ATP the γ effect to E1 not or with αβ but the of the γ basis for the effects of γ is that a for and gradients across renal cells. Both γ variants are in the A.G. Karlish S.J.D. Blostein R. J. 2001; PubMed Scopus Google is in the regions of the that the affinity for ATP by γ to pump and the decrease in Na+ affinity to ATP and an Accordingly, its effect γ to the pump with the to ATP and be by an increase in the Na+ concentration by Garty H. F. N. Goldshleger R. Karlish S.J.D. J. 2001; Scholar) have that in regions with γ in the affinity for Na+ is C. L. S. C. Doucet A. J. Physiol. Physiol. PubMed Google in and the renal pump is associated with CHIF the effect of γ on K′Na P. S. Garty H. K. J. 2001; PubMed Scopus Google the affinity for Na+ at least these may be for have an important role in Na+ and K+ It is not in to the γ the increase in Na+ affinity by CHIF a decrease in the affinity for K+ as a of cytoplasmic Na+ activation. important role of γ in renal secondary to its and is by results the functional of Gly-41 to evidence that the G41R γ with the αβ pump, in the of γ both to to the cell surface and to pump The the γ by van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google In addition, that αβ pump trafficking is not The of the of renal Mg2+-wasting with of γ of is It is that the of in and the different regions of the are and ATP affinity of αβ pumps by of by γ may decrease pump and to secondary in Mg2+ Accordingly, renal Mg2+-wasting seen in the dominant by van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google Scholar) to be secondary to the of γ of The primary to be is the increase in renal and that is in these van H. de M. Van den Nat. Genet. 2000; PubMed Scopus Google The in this were with cells. The to γ trafficking and of the γ effects by G41R replacement are different in to be are to this of γ in renal cells. and for on the and for the of

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