Na+-dependent Inactivation of the Retinal Cone/Brain Na+/Ca2+-K+ Exchanger NCKX2

The SLC24 gene family Na+/Ca2+-K+ exchangers (NCKX) are bidirectional plasma membrane transporters whose main function is the extrusion of Ca2+ from the cytosol. In this study, we used human embryonic kidney 293 cells expressing human retinal cone/brain NCKX2 to examine its Na+ affinity and kinetic parameters of Ca2+ transport. With the use of the ionophore gramicidin to control alkali cation concentrations across the plasma membrane, application of high intracellular Na+ promoted large NCKX2-mediated increases in intracellular free Ca2+ in the 15–20 μm range; this also resulted in inactivation of NCKX2 transport, the first description of this novel kinetic state. The affinity of NCKX2 for internal Na+ was found to be sigmoidal, with a Hill coefficient of 2.6 and Kd = 50 mm. The time-dependent (t½ ∼ 40s) inactivation of NCKX2 required high intracellular Na+ levels (Kd > 50 mm) as well as high occupancy of the extracellular Ca2+-binding site. Also reported are two residues whose substitution resulted in an increase in internal Na+ affinity to values of ∼19 mm; these mutants also displayed enhanced inactivation, suggesting that inactivation requires binding of Na+ to its intracellular transport sites. These findings are the first report of a regulatory kinetic state of Ca2+ transport via NCKX2 Na+/Ca2+-K+ exchangers that may play a prominent role in regulation of Ca2+ extrusion in cellular environments such as neuronal synapses that experience frequent and dynamic Ca2+ fluxes. The SLC24 gene family Na+/Ca2+-K+ exchangers (NCKX) are bidirectional plasma membrane transporters whose main function is the extrusion of Ca2+ from the cytosol. In this study, we used human embryonic kidney 293 cells expressing human retinal cone/brain NCKX2 to examine its Na+ affinity and kinetic parameters of Ca2+ transport. With the use of the ionophore gramicidin to control alkali cation concentrations across the plasma membrane, application of high intracellular Na+ promoted large NCKX2-mediated increases in intracellular free Ca2+ in the 15–20 μm range; this also resulted in inactivation of NCKX2 transport, the first description of this novel kinetic state. The affinity of NCKX2 for internal Na+ was found to be sigmoidal, with a Hill coefficient of 2.6 and Kd = 50 mm. The time-dependent (t½ ∼ 40s) inactivation of NCKX2 required high intracellular Na+ levels (Kd > 50 mm) as well as high occupancy of the extracellular Ca2+-binding site. Also reported are two residues whose substitution resulted in an increase in internal Na+ affinity to values of ∼19 mm; these mutants also displayed enhanced inactivation, suggesting that inactivation requires binding of Na+ to its intracellular transport sites. These findings are the first report of a regulatory kinetic state of Ca2+ transport via NCKX2 Na+/Ca2+-K+ exchangers that may play a prominent role in regulation of Ca2+ extrusion in cellular environments such as neuronal synapses that experience frequent and dynamic Ca2+ fluxes. Among the multitude of proteins that handle Ca2+ fluxes across the plasma membrane of excitable tissue, Na+/Ca2+ exchangers play a prominent role in maintaining intracellular Ca2+ homeostasis. These proteins belong to one of two gene families: SLC8, the members of which mediate electrogenic exchange of three Na+ ions for one Ca2+ ion (1Quednau B.D. Nicoll D.A. Philipson K.D. Pfluegers Arch. Eur. J. Physiol. 2004; 447: 543-548Crossref PubMed Scopus (99) Google Scholar), and SLC24, the members of which mediate electrogenic exchange of four Na+ ions for one Ca2+ ion and one K+ ion (2Schnetkamp P.P.M. Pfluegers Arch. Eur. J. Physiol. 2004; 447: 683-688Crossref PubMed Scopus (86) Google Scholar). The SLC8 gene family is composed of three distinct proteins: the Na+/Ca2+ exchanger (NCX) 3The abbreviations used are: NCX, Na+/Ca2+ exchanger; NCKX, Na+/Ca2+-K+ exchanger; HEK293, human embryonic kidney 293 cells; TAPS, 3-[tris(hydroxymethyl)methyl]aminopropanesulfonic acid; HEDTA, N-(2-hydroxyethyl)ethylenediaminetriacetic acid; PMCA, plasma membrane Ca2+-ATPase; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; Tg, thapsigargin; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone. NCX1, which has widespread tissue distribution in animals, with strong expression in the heart and spleen; and NCX2 and NCX3, which are restricted to the brain and skeletal muscle (3Lee S.L. Yu A.S. Lytton J. J. Biol. Chem. 1994; 269: 14849-14852Abstract Full Text PDF PubMed Google Scholar, 4Li Z. Matsuoka S. Hryshko L.V. Nicoll D.A. Bersohn M.M. Burke E.P. Lifton R.P. Philipson K.D. J. Biol. Chem. 1994; 269: 17434-17439Abstract Full Text PDF PubMed Google Scholar, 5Nicoll D.A. Quednau B.D. Qui Z. Xia Y.R. Lusis A.J. Philipson K.D. J. Biol. Chem. 1996; 271: 24914-24921Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar). On the other hand, the SLC24 gene family is composed of five members. The Na+/Ca2+-K+ exchanger (NCKX) NCKX1 was first reported in retinal rod outer segments and is the isoform on which most extensive physiological studies have been performed (6Cervetto L. Lagnado L. Perry R.J. Robinson D.W. McNaughton P.A. Nature. 1989; 337: 740-743Crossref PubMed Scopus (286) Google Scholar, 7Schnetkamp P.P.M. Basu D.K. Szerencsei R.T. Am. J. Physiol. 1989; 257: C153-C157Crossref PubMed Google Scholar, 8Schnetkamp P.P.M. Cell Calcium. 1995; 18: 322-330Crossref PubMed Scopus (48) Google Scholar). NCKX2 transcripts have been reported in the brain and retina (9Tsoi M. Rhee K.H. Bungard D. Li X.F. Lee S.L. Auer R.N. Lytton J. J. Biol. Chem. 1998; 273: 4155-4162Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 10Prinsen C.F.M. Szerencsei R.T. Schnetkamp P.P.M. J. Neurosci. 2000; 20: 1424-1434Crossref PubMed Google Scholar, 11Prinsen C.F.M. Cooper C.B. Szerencsei R.T. Murthy S.K. Demetrick D.J. Schnetkamp P.P.M. Adv. Exp. Med. Biol. 2002; 514: 237-251Crossref PubMed Scopus (15) Google Scholar, 12Paillart C. Winkfein R.J. Schnetkamp P.P.M. Korenbrot J.I. J. Gen. Physiol. 2007; 129: 1-16Crossref PubMed Scopus (18) Google Scholar), and recent emergent evidence indicates that this isoform is important for regulation of Ca2+ levels in synaptic terminals (13Lee S.H. Kim M.H. Park K.H. Earm Y.E. Ho W.K. J. Neurosci. 2002; 22: 6891-6899Crossref PubMed Google Scholar, 14Kim M.H. Lee S.H. Park K.H. Ho W.K. Lee S.H. J. Neurosci. 2003; 23: 11673-11680Crossref PubMed Google Scholar, 15Li X.F. Kiedrowski L. Tremblay F. Fernandez F.R. Perizzolo M. Winkfein R.J. Turner R.W. Bains J.S. Rancourt D.E. Lytton J. J. Biol. Chem. 2006; 281: 6273-6282Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). NCKX3 and NCKX4 transcripts are also found in the brain, but have also been localized to smooth muscle of the aorta, uterus, and intestine (16Kraev A. Quednau B.D. Leach S. Li X.F. Dong H. Winkfein R. Perizzolo M. Cai X. Yang R. Philipson K.D. Lytton J. J. Biol. Chem. 2001; 276: 23161-23172Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 17Li X.F. Kraev A.S. Lytton J. J. Biol. Chem. 2002; 277: 48410-48417Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Recently, NCKX5 transcripts have been reported to be rich in melanin-containing tissues, viz. the eye and skin (18Lamason R.L. Mohideen M.A. Mest J.R. Wong A.C. Norton H.L. Aros M.C. Jurynec M.J. Mao X. Humphreville V.R. Humbert J.E. Sinha S. Moore J.L. Jagadeeswaran P. Zhao W. Ning G. Makalowska I. McKeigue P.M. O'Donnell D. Kittles R. Parra E.J. Mangini N.J. Grunwald D.J. Shriver M.D. Canfield V.A. Cheng K.C. Science. 2005; 310: 1782-1786Crossref PubMed Scopus (790) Google Scholar). Most of the available studies on NCKX structure have been carried out on The NCKX proteins to a structure of two of five and the an of five and five segments a large Szerencsei R.T. Winkfein R.J. Schnetkamp P.P.M. 2003; PubMed Scopus Google Scholar). also have a that is for plasma membrane a large extracellular the is also Schnetkamp P.P.M. 2003; PubMed Scopus Google Scholar). NCKX and proteins in two internal the and the and of human NCKX2 have been to be important for the transport function of NCKX2 and for its affinity for Ca2+ and K+ R.J. Szerencsei R.T. Perizzolo M. L. Schnetkamp P.P.M. 2003; PubMed Scopus Google Scholar, Szerencsei R.T. Schnetkamp P.P.M. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, Szerencsei R.T. Schnetkamp P.P.M. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google in these segments are in in Szerencsei R.T. Winkfein R.J. Schnetkamp P.P.M. 2005; PubMed Scopus (15) Google Scholar). exchange of Ca2+ is a for Na+ other alkali cation Nature. PubMed Scopus Google Scholar, P.P.M. J. Physiol. Scopus Google Scholar). to the residues for Na+ binding and transport are we to an that to control internal Na+ to the affinity of the exchanger for Na+/Ca2+ exchangers to are of bidirectional transport of Ca2+ across the plasma membrane, most that have been to Na+/Ca2+ exchange in cells on the of this study, we to examine the of the of exchange of human which is the of transport that is of physiological we out to the of other cellular in the we we that NCKX2 is a Ca2+ extrusion but a kinetic state that is and The have been in Szerencsei R.T. Schnetkamp P.P.M. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, C.B. Szerencsei R.T. Schnetkamp P.P.M. 2000; PubMed Google Scholar), and are used from for NCKX embryonic kidney 293 cells expressing the of NCKX2 C.F.M. Szerencsei R.T. Schnetkamp P.P.M. J. 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Schnetkamp P.P.M. 2003; PubMed Scopus Google in with μm and for The cells for and with a of and The cells in and to of The was and and of used to of and was of and the carried out in was used in of the Ca2+ cells was in the of an and was and the of ion concentrations as the alkali cation concentrations across the plasma membrane, the alkali cation ionophore gramicidin was to the to the of the other also the as The first was μm which an increase in to Ca2+ binding to Ca2+ this of the of and was also in Ca2+ cells and was of On the other hand, in in which was to the to an in which of Ca2+ from Ca2+ in the in the of the increase in the of the was to the values the which was in the the of was in the of to the Ca2+ and to a which was used to the values for the In the carried out with μm the Ca2+ was the of and to the to Ca2+ in this was to the for NCKX2 and on exchange in cells on the cells in a free of Na+ intracellular Ca2+ the of we that the of NCKX, as the of Ca2+ with as cells in with the that the Ca2+ of cells from this that the to in we out to to to that the exchange of NCKX is on internal this we the cation ionophore gramicidin to cation concentrations across the plasma membrane and to to control internal Na+ concentrations C.B. Szerencsei R.T. Schnetkamp P.P.M. 2000; PubMed Google Scholar, P.P.M. J.E. Szerencsei R.T. Am. J. Physiol. 1995; 269: PubMed Google Scholar), the in exchange in cells with the of the Ca2+ and in The cells in a and with μm and μm was to the which a increase in that to that and the of μm a free Ca2+ in the of was to the which a increase in free that a The was but in a with in of In this the of mm) was required to exchange and to intracellular Ca2+ with the of NCKX for cells in a with and with the of μm was to the but the the the of which the to the in and to that the exchanger is on cells in a with and and with μm The of μm a increase in which for and the was the of this we to control Na+ concentrations in the and the affinity of the exchanger for In cells in in with and with μm gramicidin exchange was the of to the of μm this of Ca2+ was to Ca2+ the exchanger to Ca2+ internal Ca2+ of Ca2+ in cells requires the of concentrations of Ca2+ D. C. S. F. Pfluegers Arch. Eur. J. 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Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), suggesting that internal Ca2+ was to a in the of the gramicidin in its we two other intracellular Ca2+ from with a reported Kd of and with a Kd of On the of of increases these Ca2+ and we we that the of with to the of in to intracellular free Ca2+ in the of 15–20 in we the of the Ca2+ which the of the increase the of NCKX2 from of and Na+ to cells in in an increase in internal Ca2+ that cells Na+/Ca2+ exchange have other for intracellular Ca2+ viz. the plasma membrane the sarco/endoplasmic reticulum and The of these to regulation of intracellular free Ca2+ in The was out the in with the to was with μm and Ca2+ was with the carbonyl cyanide to the cells in the the of the with to exchange to the in internal Ca2+ to to the of μm to cells resulted in a increase in the of Ca2+ via exchange with cells with gramicidin the of the resulted in of the exchange of the increase as but the most of exchange was with cells with μm The of with cells with a of of with for cells These that these to to regulation of Ca2+ in and to the of the we the of to examine the of Ca2+ SERCA, and but out in as that the use of gramicidin to strong of the cytosol. was the of the increase was to the of is also to the of the exchanger P.P.M. 1995; PubMed Scopus Google Scholar). the of the increase in cells with in cells with μm with μm the increase the of Na+ in cells was with that in control the > = that to the of Ca2+ in cells On the other hand, the cells with and in = suggesting in are the of large NCKX2-mediated in to in that we the of the cells with μm and μm to exchange the of NCKX2 for the affinity of NCKX2 for we the of in the of concentrations of Na+ to the of the of in the of μm free Ca2+ In Na+ concentrations in intracellular and and this was of the use of The of μm free Ca2+ to be to of Ca2+ Na+ the of of NCKX2 in to the of the The Kd of NCKX2 for internal Na+ was 50 = and the Hill a coefficient of that NCKX Na+ ions in transport is the first reported of the Kd of NCKX for intracellular be with values reported for the Kd for extracellular Na+ of human and NCKX2 in the Hill coefficient of Schnetkamp P.P.M. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), NCKX2 in cells Hill coefficient of H. R.J. Lytton J. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), and in rod NCKX1 Hill coefficient of P.P.M. J. Gen. Physiol. PubMed Scopus Google Scholar, P.P.M. Szerencsei R.T. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of examine the exchange of NCKX2 we cells with Ca2+ via the exchange of of NCKX2 the of in the of μm free and the the was to the to the Ca2+ across the plasma The levels the of of extrusion of Ca2+ from the via NCKX2 this with in the and of the of in cells that in control cells with and a of Ca2+ that the in in the cells was the but in in that and we to the of cells with and to Ca2+ a of Na+ concentrations and found that the of Ca2+ extrusion with Na+ concentrations was as we that Ca2+ extrusion as the of Na+ was to kinetic In the in the of and Na+ promoted Ca2+ the of of the was the and the the of the that the exchanger and was to internal of of the that intracellular Na+ in resulted in the inactivation of the of exchange of Na+ and the intracellular of the we the of inactivation of In cells with Ca2+ via the exchanger the of Na+ in the of μm free was to extracellular Ca2+ and to Ca2+ from the via the the from the of cells for The of Ca2+ with and was that inactivation of the exchanger with a we the of inactivation These the inactivation required to and was the was with high free Ca2+ for of to to high levels of internal Na+ Na+ was the inactivation have been to the of a we the of the Ca2+ of cells with Na+ in the of μm free this of Na+ was to inactivation, as in in in the of NCKX2 was in Ca2+ of the with of the in we in the of of Ca2+ in this and cells with Ca2+ the of Na+ in the of μm free and was to μm was to Ca2+ in the the from four Ca2+ and to the of Ca2+ in the Ca2+ in the in with the Ca2+ application of of Ca2+ via These also was a dynamic NCKX2 Ca2+ the and Ca2+ from the cytosol. The also that the of of NCKX2 to as the of the Ca2+ with of the of Ca2+ the NCKX2 on the inactivation of the exchanger may have been to application of high Na+ the intracellular of the with Ca2+ the we the of inactivation of NCKX2 in cells with values of was a to the inactivation, the Ca2+ levels the inactivation Ca2+ the via the and Na+ with Ca2+ for the intracellular binding we the as the of Ca2+ was inactivation a of cells with μm free In the cells with Ca2+ via the exchange of NCKX2 the of The cells that been to μm free Ca2+ to the of to μm free Ca2+ used in displayed a of Ca2+ from the of Ca2+ that inactivation of NCKX2 required high intracellular Na+ and high extracellular the also Na+ and we the of in the inactivation this we cells with the of the and carried out the but we large in intracellular the of and the of of evidence that the inactivation of the exchanger was and was that be the Na+ in the was the cells with Ca2+ the exchange of NCKX2 in of and 50 a of the was with to the Na+ from to mm. a time-dependent of inactivation In with the state of exchange was the that the high Na+ was to the binding and to Ca2+ the was with of the levels with of the in suggesting that to high intracellular Na+ was to the exchanger and that the inactivation required to that with of exchange resulted in of with the to a the Ca2+ the of in was the of the with NCKX2 an of the to for NCKX2 inactivation to be to occupancy of the internal binding of NCKX2 with this be to have NCKX2 mutants with Na+ are in the of the NCKX2 mutants reported R.J. Szerencsei R.T. Perizzolo M. L. Schnetkamp P.P.M. 2003; PubMed Scopus Google for in Na+ affinity the in found to be for this study, as resulted in a increase in affinity for internal we reported that a which the of of is important for the binding and transport of Ca2+ and K+ Szerencsei R.T. Schnetkamp P.P.M. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of with in the affinity of the exchanger for K+ and Ca2+ and In this study, we for internal Na+ affinity the concentrations with in the affinity for intracellular Na+ was with the the Kd was = as to 50 for NCKX2 The Hill coefficient was to a of as to 2.6 for whose substitution we also found to increase the affinity of the exchanger for Na+ was its substitution to also resulted in Na+ with Kd = = and a Hill coefficient of the values of the three NCKX2 as the of the in NCKX2 and the the of the was we that NCKX2 to high intracellular we that mutants with affinity for intracellular Na+ inactivation of the of exchange Na+ concentrations that this was the we inactivation of NCKX2 intracellular Na+ was to the and mutants displayed Ca2+ intracellular Na+ was to mm. that with the of Ca2+ the of cells with the of Ca2+ as cells with with the of intracellular Ca2+ increase the of the exchange the mutants Na+ and intracellular Ca2+ to the the of cells the of Ca2+ to Ca2+ also in we that a affinity for Ca2+ and K+ Szerencsei R.T. Schnetkamp P.P.M. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), this for this of this to Ca2+ in exchange was an the in intracellular Ca2+ The SLC24 gene family of NCKX Na+/Ca2+-K+ exchangers bidirectional and electrogenic Ca2+ The transport of Ca2+ these is on the of and K+ as well as membrane NCKX a high and a large to intracellular free Ca2+ a large of free Ca2+ concentrations and intracellular free Ca2+ in the P.P.M. Li Basu D.K. Szerencsei R.T. J. Biol. Chem. Full Text PDF PubMed Google Scholar). we have a for the affinity of the human retinal cone/brain exchanger NCKX2 for Na+ and to examine the of Ca2+ extrusion from the in the we a novel of inactivation of Ca2+ transport. that this kinetic an and of the exchanger as a regulatory to of intracellular Ca2+ to The of the gramicidin to control alkali cation concentrations across the plasma membrane has and for and the affinity of the exchanger for The Na+ of cells is which is the of Na+ the of exchanger on the intracellular Na+ to Ca2+ be of the of the exchanger to in Na+ concentrations in this In the of gramicidin and high NCKX2 was to intracellular free Ca2+ to high levels of 15–20 the use of the affinity Ca2+ to of the The dynamic Ca2+ fluxes for cells expressing NCKX2 are a of of the NCKX2 in this as are to in for Ca2+ fluxes and NCKX in the outer segments of retinal rod P.P.M. J.E. Szerencsei R.T. Am. J. Physiol. 1995; 269: PubMed Google Scholar, P.P.M. Li Basu D.K. Szerencsei R.T. J. Biol. Chem. Full Text PDF PubMed Google and C. Winkfein R.J. Schnetkamp P.P.M. Korenbrot J.I. J. Gen. Physiol. 2007; 129: 1-16Crossref PubMed Scopus (18) Google NCKX2 and have NCKX mediate large increases in intracellular the Na+ is as to Ca2+ a of the Ca2+ is the exchanger intracellular Na+ is that a dynamic of Ca2+ via the exchanger and Ca2+ is intracellular Ca2+ levels a On the of we carried out with the two a reported Kd for Ca2+ of and Kd for Ca2+ of we that the which Ca2+ was Kim M.H. R. Ho W.K. Lee S.H. J. Neurosci. 2005; PubMed Scopus Google found a Ca2+ synaptic Na+/Ca2+ exchange a in Ca2+ with Ca2+ levels μm the Ca2+ is in in of Ca2+ to are the for Ca2+ intracellular Ca2+ μm J. Park 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the of Ca2+ which to Ca2+ in cells was the as that required to inactivation of the the of an and the exchanger the plasma an the plasma membrane Na+/Ca2+ exchanger and has been to mediate inactivation of exchange of J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). out this we that such is the for this from of NCKX2 the use of gramicidin the that Na+ was on of the membrane with and exchange in the may have been of of Na+ on the of the this to be the out the in a of high we to Na+ and Ca2+ the binding of as was in studies of Na+/Ca2+-K+ exchange in in rod outer segments P.P.M. Li Basu D.K. Szerencsei R.T. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of findings the inactivation was time-dependent as in was have been In with this we have also time-dependent of inactivation intracellular Na+ from to inactivation extracellular Ca2+ was to μm was be that the Ca2+ and the Ca2+ in the in the of high internal the of inactivation for NCKX2 is in to inactivation for the Na+/Ca2+ exchanger D.W. Matsuoka S. A. J. Gen. Physiol. PubMed Scopus Google Scholar), for which was that the state the exchanger transport are to high Na+ on the and that requires high extracellular Ca2+ as D.W. Matsuoka S. A. J. Gen. Physiol. PubMed Scopus Google that inactivation of the exchanger with extracellular Ca2+ the exchanger binding the which from to high internal Na+ on the the that the with the NCKX2 mutants and that inactivation of NCKX2 is on its affinity for as these mutants enhanced inactivation intracellular with affinity for this ion for Na+ studies have reported on residues important for Na+ transport of NCKX transporters on residues in the of transporters important for Na+ transport. and are and in the of and NCKX in the and of Na+ that these two residues may of the of NCKX and reported that is one of the two most important residues with that the Ca2+ affinity of NCKX transporters Szerencsei R.T. Schnetkamp P.P.M. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). from on retinal rod outer segments that the NCKX1 exchanger that the NCKX1 exchanger in of which P.P.M. Basu D.K. Li Szerencsei R.T. J. Biol. Chem. Full Text PDF PubMed Google Scholar, P.P.M. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). the of kinetic of the NCKX2 exchanger and of the for the of inactivation to high extracellular Ca2+ and high intracellular Na+ is the of the regulatory of NCKX1 and NCKX2 and to are The in this and the of cells to NCKX proteins levels with found in in rod and be to the regulatory and kinetic of NCKX of NCKX2 may be a regulatory that physiological evidence to NCKX2 an important Ca2+ in neuronal synaptic terminals (13Lee S.H. Kim M.H. Park K.H. Earm Y.E. Ho W.K. J. Neurosci. 2002; 22: 6891-6899Crossref PubMed Google Scholar, 14Kim M.H. Lee S.H. Park K.H. Ho W.K. Lee S.H. J. Neurosci. 2003; 23: 11673-11680Crossref PubMed Google Scholar, 15Li X.F. Kiedrowski L. Tremblay F. Fernandez F.R. Perizzolo M. Winkfein R.J. Turner R.W. Bains J.S. Rancourt D.E. Lytton J. J. Biol. 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