Molecular Cloning of a Third Member of the Potassium-dependent Sodium-Calcium Exchanger Gene Family,NCKX3

We describe here the identification and characterization of a novel member of the family of K+-dependent Na+/Ca2+ exchangers, NCKX3(gene SLC24A3). Human NCKX3 encodes a protein of 644 amino acids that displayed a high level of sequence identity to the other family members, rod NCKX1 and cone/neuronal NCKX2, in the hydrophobic regions surrounding the “α -repeat” sequences thought to form the ion-binding pocket for transport. Outside of these regions NCKX3 showed no significant identity to other known proteins. As anticipated from this sequence similarity, NCKX3 displayed K+-dependent Na+/Ca2+exchanger activity when assayed in heterologous expression systems, using digital imaging of fura-2 fluorescence, electrophysiology, or radioactive 45Ca2+ uptake. The N-terminal region of NCKX3, although not essential for expression, increased functional activity at least 10-fold and may represent a cleavable signal sequence. NCKX3 transcripts were most abundant in brain, with highest levels found in selected thalamic nuclei, in hippocampal CA1 neurons, and in layer IV of the cerebral cortex. Many other tissues also expressed NCKX3 at lower levels, especially aorta, uterus, and intestine, which are rich in smooth muscle. The discovery of NCKX3 thus expands the K+-dependent Na+/Ca2+ exchanger family and suggests this class of transporter has a more widespread role in cellular Ca2+ handling than previously appreciated. We describe here the identification and characterization of a novel member of the family of K+-dependent Na+/Ca2+ exchangers, NCKX3(gene SLC24A3). Human NCKX3 encodes a protein of 644 amino acids that displayed a high level of sequence identity to the other family members, rod NCKX1 and cone/neuronal NCKX2, in the hydrophobic regions surrounding the “α -repeat” sequences thought to form the ion-binding pocket for transport. Outside of these regions NCKX3 showed no significant identity to other known proteins. As anticipated from this sequence similarity, NCKX3 displayed K+-dependent Na+/Ca2+exchanger activity when assayed in heterologous expression systems, using digital imaging of fura-2 fluorescence, electrophysiology, or radioactive 45Ca2+ uptake. The N-terminal region of NCKX3, although not essential for expression, increased functional activity at least 10-fold and may represent a cleavable signal sequence. NCKX3 transcripts were most abundant in brain, with highest levels found in selected thalamic nuclei, in hippocampal CA1 neurons, and in layer IV of the cerebral cortex. Many other tissues also expressed NCKX3 at lower levels, especially aorta, uterus, and intestine, which are rich in smooth muscle. The discovery of NCKX3 thus expands the K+-dependent Na+/Ca2+ exchanger family and suggests this class of transporter has a more widespread role in cellular Ca2+ handling than previously appreciated. Na+/Ca2+ exchanger expressed sequence tags kilobase pair 3-(N-morpholino)propane-sulfonic acid Na+/Ca2+ + K+ exchanger polymerase chain reaction reverse transcription-coupled polymerase chain reaction Plasma membrane Na+/Ca2+ exchangers are an important component of intracellular Ca2+ homeostasis and have been extensively studied in various cell systems (1Blaustein M.P. Lederer W.J. Physiol. Rev. 1999; 79: 763-854Crossref PubMed Scopus (1443) Google Scholar). Na+/Ca2+ exchangers are encoded by a protein superfamily present in organisms ranging from bacteria to man (2Philipson K.D. Nicoll D.A. Annu. Rev. Physiol. 2000; 62: 111-133Crossref PubMed Scopus (442) Google Scholar). All the members of this family share sequence similarity in two hydrophobic and internally homologous domains, commonly referred to as α-repeats (3Schwarz E.M. Benzer S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10249-10254Crossref PubMed Scopus (180) Google Scholar). Two groups within the Na+/Ca2+ exchanger superfamily have been characterized so far in considerable detail and consist of structurally and functionally distinct proteins. Na+/Ca2+ exchangers (NCX)1 are thought to catalyze the extrusion of one intracellular Ca2+ ion in exchange for three extracellular Na+ ions (Ref. 1Blaustein M.P. Lederer W.J. Physiol. Rev. 1999; 79: 763-854Crossref PubMed Scopus (1443) Google Scholar but see Ref. 4Fujioka Y. Komeda M. Matsuoka S. J. Physiol. ( Lond. ). 2000; 523: 339-351Crossref PubMed Scopus (83) Google Scholar). Na+/Ca2+ + K+ exchangers (NCKX), on the other hand, are thought to transport one intracellular Ca2+ and one K+ ion in exchange for four extracellular Na+ ions (5Schnetkamp P.P.M. Cell Calcium. 1995; 18: 322-330Crossref PubMed Scopus (47) Google Scholar).The family of exchangers by the Na+/Ca2+ from D.A. S. K.D. PubMed Scopus Google which a role in the of by the Ca2+ that at the of also expressed in a of other tissues Lederer W.J. J. Physiol. PubMed Google J. J. PubMed Google Nicoll D.A. K.D. J. Physiol. 1997; PubMed Google an important role in the of cell The expression of has been to the of a J. 1997; PubMed Scopus Google K.D. J. J. Physiol. Google A. S. J. PubMed Scopus Google Scholar). a of in the intracellular of of the which are also expressed in a Lederer W.J. J. Physiol. PubMed Google J. J. PubMed Google Nicoll D.A. K.D. J. Physiol. 1997; PubMed Google Scholar). have of the of which (2Philipson K.D. Nicoll D.A. Annu. Rev. Physiol. 2000; 62: 111-133Crossref PubMed Scopus (442) Google A. K.D. M. J. Physiol. 1999; PubMed Scopus Google Scholar). The protein family two other members, of expression to and Nicoll D.A. K.D. J. Physiol. 1997; PubMed Google Matsuoka S. Nicoll D.A. K.D. J. PubMed Google D.A. K.D. J. PubMed Scopus Google Scholar). All three share a high of sequence especially within the domains, and are to share the to have two of hydrophobic by a intracellular The hydrophobic are thought to in the the ion Nicoll D.A. K.D. J. PubMed Scopus Google Scholar). the three functional when assayed in heterologous expression systems K.D. J. Physiol. PubMed Google M. J. Physiol. PubMed Google Scholar).The in the Na+/Ca2+exchanger superfamily by the exchanger from rod NCKX1 from A. U. J. PubMed Scopus Google more from other and man S. S. P.P.M. J. J. Physiol. 2000; Google P.P.M. 1999; PubMed Scopus Google P.P.M. Sci. Google Scholar). protein a role in the of the (5Schnetkamp P.P.M. Cell Calcium. 1995; 18: 322-330Crossref PubMed Scopus (47) Google Scholar). the ion of the are and Na+ and Ca2+ ions Ca2+ homeostasis these of membrane and and NCKX1 the by which Ca2+ from rod a not by a with the of and has been that NCKX1 the of four Na+ ions in exchange for the of one Ca2+ and one K+ ion PubMed Scopus Google P.P.M. J. Physiol. PubMed Google from are in amino acid NCKX1 sequence of to in the two an extracellular one the and a one the of the NCKX1 has been to have a of as although amino acid sequence similarity and to the two as The of NCKX1 from S. S. P.P.M. J. J. Physiol. 2000; Google also the of in this which by the of four at the of the intracellular the region of but not the region in for a functionally protein when expressed in heterologous systems S. S. P.P.M. J. J. Physiol. 2000; Google P.P.M. 1999; PubMed Scopus Google have the of K+-dependent in tissues other than J. PubMed Google M. A. J. PubMed Google Scholar). has expression of NCKX1 in of M. E.M. J. J. Physiol. 1999; Google and a K+-dependent Na+/Ca2+ exchanger in and P.P.M. J. 2000; PubMed Google M. J. J. Scopus Google Scholar). sequence of the of as has with similarity to the family (2Philipson K.D. Nicoll D.A. Annu. Rev. Physiol. 2000; 62: 111-133Crossref PubMed Scopus (442) Google E.M. Benzer S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10249-10254Crossref PubMed Scopus (180) Google M. J. J. Scopus Google Scholar). Two of these have been characterized functionally P.P.M. J. 2000; PubMed Scopus Google P.P.M. J. Cell 1999; PubMed Scopus Google Scholar). of expression using from regions of sequence of has for as members of the family S. S. P.P.M. J. J. Physiol. 2000; Google Scholar). of the sequence of the J. M. A. J. PubMed Scopus Google M. J. PubMed Scopus Google family member on the although has not been characterized of the sequence of the J. M. A. J. PubMed Scopus Google M. J. PubMed Scopus Google family member on the although has not been characterized to the that the family the of and that the encoded are an essential component of intracellular Ca2+ homeostasis in and more role for in of cellular Ca2+ homeostasis has to has been no of expression in tissues other than P.P.M. J. 2000; PubMed Google this have from in three a novel member of the K+-dependent Na+/Ca2+exchanger We that transcripts from this are in and other tissues and when expressed in NCKX3 encodes a K+-dependent this have the and characterization of a a member of the family of K+-dependent the other two members, rod NCKX1 and cone/neuronal NCKX2, NCKX3 K+-dependent activity when with the with ion or with not with Na+ and an for of the functional NCKX3 with in the as also on the of transport. with the high of amino acid sequence similarity to which has been to transport Na+ in exchange for K+ and PubMed Scopus Google P.P.M. J. Physiol. PubMed Google that NCKX3 has a with the the regions of the in the pocket for ion D.A. M. Y. K.D. J. 1999; PubMed Scopus Google D.A. Matsuoka S. K.D. J. PubMed Scopus Google Scholar). on a of NCKX1 and a have regions also the transport for K+-dependent P.P.M. J. 2000; PubMed Scopus Google Scholar). of the sequences NCKX3 and these the high sequence similarity anticipated within the NCKX3 more in these regions than the these of to or with NCKX3 in to and thus this sequence on the amino acids to to the of the K+-dependent class of Na+/Ca2+ as as in a for NCKX3 that to previously for other family members The NCKX3 protein with a functionally region that may a in a to that for M. Nicoll D.A. K.D. M. 1995; PubMed Scopus Google J. 1995; PubMed Scopus Google J. J. 1995; PubMed Scopus Google Scholar). The of this region in the expressed protein the level of functional expression of NCKX3 K+-dependent Na+/Ca2+ exchange activity when assayed using fura-2 digital the expressed activity in in and not a significant in the of protein expression, the NCKX3 protein the N-terminal hydrophobic sequence may or to the membrane more than the protein this NCKX3 protein of a extracellular at the by a of a and a of hydrophobic The which to on a to NCKX1 and sequences for protein using of have that the hydrophobic region of that of four and a that the membrane D.A. M. Y. K.D. J. 1999; PubMed Scopus Google A. M. J. 2000; PubMed Scopus Google Y. A. M. 1999; PubMed Scopus Google Scholar). of NCKX3 suggests a with the from the protein which on the extracellular of the The of a and the that the K+-dependent Na+/Ca2+ exchangers may have a from of the to for NCKX3 are in and in sequence on in The two of the NCKX3 are the which the especially the are the of in to the of other Na+/Ca2+ exchanger The NCKX1 share an that from the the by also see A. PubMed Scopus Google Scholar and P.P.M. PubMed Scopus Google Scholar). the sequence of NCKX3 the of the hydrophobic for NCKX3 and from the NCKX1 and or the distinct and the sequence similarity within the NCKX3 have in a and from other and family of expression of NCKX3 transcripts in tissues in and by and in by these that NCKX3 most expressed in various in more detail in of using in which a The highest levels of NCKX3 were found in in distinct of the by the CA1 of the and of layer from of and in M. J. J. Scopus Google J. PubMed Scopus Google Scholar). for of these exchangers were also abundant in but the for All three exchangers were present in hippocampal but NCKX3 in CA1 the exchanger a NCKX3 and expression in the NCKX3 from the and from the nuclei, of NCKX3 expression in to other K+-dependent the of transcripts in tissues other than brain, although at lower The to and although of this may have been to the in which a of in the of and to a of to in the of the or to the in the The tissues that the most abundant level of NCKX3 brain, were rich in smooth as aorta, uterus, and Many other tissues expressed lower levels, but and to for of expression more that of than of the other family members, which are thought to have expression NCKX1 in in and and in and muscle. The of NCKX3 in cell of the or has to have been no of K+-dependent Na+/Ca2+ exchange activity in these tissues or cell present the of the expression for Na+/Ca2+ exchanger family members are The in brain, at least four Na+/Ca2+ exchanger NCKX2, and are present at high levels, that of tissues or cell with or in the of these exchangers, important The in transport and an for exchangers to Ca2+ homeostasis in the the membrane are lower than this to the expression of NCKX1 in rod may in other role for exchanger in the transport of of Ca2+ M. M. M. S. 2000; PubMed Scopus Google Scholar). We have not NCKX3 transport that NCKX3 activity although these no significant on the of or and J. that more with the transport of than with the of other family to the of for the Na+/Ca2+ exchanger family members the of of The of an for of Na+/Ca2+ exchangers, M. J. PubMed Scopus Google and A. S. A. S. Y. S. Y. M. Y. Y. J. 2000; PubMed Scopus (180) Google in this but are by the of the sequence in which a for of Plasma membrane Na+/Ca2+ exchangers are an important component of intracellular Ca2+ homeostasis and have been extensively studied in various cell systems (1Blaustein M.P. Lederer W.J. Physiol. Rev. 1999; 79: 763-854Crossref PubMed Scopus (1443) Google Scholar). Na+/Ca2+ exchangers are encoded by a protein superfamily present in organisms ranging from bacteria to man (2Philipson K.D. Nicoll D.A. Annu. Rev. Physiol. 2000; 62: 111-133Crossref PubMed Scopus (442) Google Scholar). All the members of this family share sequence similarity in two hydrophobic and internally homologous domains, commonly referred to as α-repeats (3Schwarz E.M. Benzer S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10249-10254Crossref PubMed Scopus (180) Google Scholar). Two groups within the Na+/Ca2+ exchanger superfamily have been characterized so far in considerable detail and consist of structurally and functionally distinct proteins. Na+/Ca2+ exchangers (NCX)1 are thought to catalyze the extrusion of one intracellular Ca2+ ion in exchange for three extracellular Na+ ions (Ref. 1Blaustein M.P. Lederer W.J. Physiol. Rev. 1999; 79: 763-854Crossref PubMed Scopus (1443) Google Scholar but see Ref. 4Fujioka Y. Komeda M. Matsuoka S. J. Physiol. ( Lond. ). 2000; 523: 339-351Crossref PubMed Scopus (83) Google Scholar). Na+/Ca2+ + K+ exchangers (NCKX), on the other hand, are thought to transport one intracellular Ca2+ and one K+ ion in exchange for four extracellular Na+ ions (5Schnetkamp P.P.M. Cell Calcium. 1995; 18: 322-330Crossref PubMed Scopus (47) Google Scholar). The family of exchangers by the Na+/Ca2+ from D.A. S. K.D. PubMed Scopus Google which a role in the of by the Ca2+ that at the of also expressed in a of other tissues Lederer W.J. J. Physiol. PubMed Google J. J. PubMed Google Nicoll D.A. K.D. J. Physiol. 1997; PubMed Google an important role in the of cell The expression of has been to the of a J. 1997; PubMed Scopus Google K.D. J. J. Physiol. Google A. S. J. PubMed Scopus Google Scholar). a of in the intracellular of of the which are also expressed in a Lederer W.J. J. Physiol. PubMed Google J. J. PubMed Google Nicoll D.A. K.D. J. Physiol. 1997; PubMed Google Scholar). have of the of which (2Philipson K.D. Nicoll D.A. Annu. Rev. Physiol. 2000; 62: 111-133Crossref PubMed Scopus (442) Google A. K.D. M. J. Physiol. 1999; PubMed Scopus Google Scholar). The protein family two other members, of expression to and Nicoll D.A. K.D. J. Physiol. 1997; PubMed Google Matsuoka S. Nicoll D.A. K.D. J. PubMed Google D.A. K.D. J. PubMed Scopus Google Scholar). All three share a high of sequence especially within the domains, and are to share the to have two of hydrophobic by a intracellular The hydrophobic are thought to in the the ion Nicoll D.A. K.D. J. PubMed Scopus Google Scholar). the three functional when assayed in heterologous expression systems K.D. J. Physiol. PubMed Google M. J. Physiol. PubMed Google Scholar). The in the Na+/Ca2+exchanger superfamily by the exchanger from rod NCKX1 from A. U. J. PubMed Scopus Google more from other and man S. S. P.P.M. J. J. Physiol. 2000; Google P.P.M. 1999; PubMed Scopus Google P.P.M. Sci. Google Scholar). protein a role in the of the (5Schnetkamp P.P.M. Cell Calcium. 1995; 18: 322-330Crossref PubMed Scopus (47) Google Scholar). the ion of the are and Na+ and Ca2+ ions Ca2+ homeostasis these of membrane and and NCKX1 the by which Ca2+ from rod a not by a with the of and has been that NCKX1 the of four Na+ ions in exchange for the of one Ca2+ and one K+ ion PubMed Scopus Google P.P.M. J. Physiol. PubMed Google Scholar). from are in amino acid NCKX1 sequence of to in the two an extracellular one the and a one the of the NCKX1 has been to have a of as although amino acid sequence similarity and to the two as The of NCKX1 from S. S. P.P.M. J. J. Physiol. 2000; Google also the of in this which by the of four at the of the intracellular the region of but not the region in for a functionally protein when expressed in heterologous systems S. S. P.P.M. J. J. Physiol. 2000; Google P.P.M. 1999; PubMed Scopus Google Scholar). have the of K+-dependent in tissues other than J. PubMed Google M. A. J. PubMed Google Scholar). has expression of NCKX1 in of M. E.M. J. J. Physiol. 1999; Google and a K+-dependent Na+/Ca2+ exchanger in and P.P.M. J. 2000; PubMed Google M. J. J. Scopus Google Scholar). sequence of the of as has with similarity to the family (2Philipson K.D. Nicoll D.A. Annu. Rev. Physiol. 2000; 62: 111-133Crossref PubMed Scopus (442) Google E.M. Benzer S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 10249-10254Crossref PubMed Scopus (180) Google M. J. J. Scopus Google Scholar). Two of these have been characterized functionally P.P.M. J. 2000; PubMed Scopus Google P.P.M. J. Cell 1999; PubMed Scopus Google Scholar). of expression using from regions of sequence of has for as members of the family S. S. P.P.M. J. J. Physiol. 2000; Google Scholar). of the sequence of the J. M. A. J. PubMed Scopus Google M. J. PubMed Scopus Google family member on the although has not been characterized of the sequence of the J. M. A. J. PubMed Scopus Google M. J. PubMed Scopus Google family member on the although has not been characterized to the that the family the of and that the encoded are an essential component of intracellular Ca2+ homeostasis in and more role for in of cellular Ca2+ homeostasis has to has been no of expression in tissues other than P.P.M. J. 2000; PubMed Google Scholar). this have from in three a novel member of the K+-dependent Na+/Ca2+exchanger We that transcripts from this are in and other tissues and when expressed in NCKX3 encodes a K+-dependent this have the and characterization of a a member of the family of K+-dependent the other two members, rod NCKX1 and cone/neuronal NCKX2, NCKX3 K+-dependent activity when with the with ion or with not with Na+ and an for of the functional NCKX3 with in the as also on the of transport. with the high of amino acid sequence similarity to which has been to transport Na+ in exchange for K+ and PubMed Scopus Google P.P.M. J. Physiol. PubMed Google that NCKX3 has a with the the regions of the in the pocket for ion D.A. M. Y. K.D. J. 1999; PubMed Scopus Google D.A. Matsuoka S. K.D. J. PubMed Scopus Google Scholar). on a of NCKX1 and a have regions also the transport for K+-dependent P.P.M. J. 2000; PubMed Scopus Google Scholar). of the sequences NCKX3 and these the high sequence similarity anticipated within the NCKX3 more in these regions than the these of to or with NCKX3 in to and thus this sequence on the amino acids to to the of the K+-dependent class of Na+/Ca2+ as as in a for NCKX3 that to previously for other family members The NCKX3 protein with a functionally region that may a in a to that for M. Nicoll D.A. K.D. M. 1995; PubMed Scopus Google J. 1995; PubMed Scopus Google J. J. 1995; PubMed Scopus Google Scholar). The of this region in the expressed protein the level of functional expression of NCKX3 K+-dependent Na+/Ca2+ exchange activity when assayed using fura-2 digital the expressed activity in in and not a significant in the of protein expression, the NCKX3 protein the N-terminal hydrophobic sequence may or to the membrane more than the protein this NCKX3 protein of a extracellular at the by a of a and a of hydrophobic The which to on a to NCKX1 and sequences for protein using of have that the hydrophobic region of that of four and a that the membrane D.A. M. Y. K.D. J. 1999; PubMed Scopus Google A. M. J. 2000; PubMed Scopus Google Y. A. M. 1999; PubMed Scopus Google Scholar). of NCKX3 suggests a with the from the protein which on the extracellular of the The of a and the that the K+-dependent Na+/Ca2+ exchangers may have a from of the to for NCKX3 are in and in sequence on in The two of the NCKX3 are the which the especially the are the of in to the of other Na+/Ca2+ exchanger The NCKX1 share an that from the the by also see A. PubMed Scopus Google Scholar and P.P.M. PubMed Scopus Google Scholar). the sequence of NCKX3 the of the hydrophobic for NCKX3 and from the NCKX1 and or the distinct and the sequence similarity within the NCKX3 have in a and from other and family of expression of NCKX3 transcripts in tissues in and by and in by these that NCKX3 most expressed in various in more detail in of using in which a The highest levels of NCKX3 were found in in distinct of the by the CA1 of the and of layer from of and in M. J. J. Scopus Google J. PubMed Scopus Google Scholar). for of these exchangers were also abundant in but the for All three exchangers were present in hippocampal but NCKX3 in CA1 the exchanger a NCKX3 and expression in the NCKX3 from the and from the nuclei, of NCKX3 expression in to other K+-dependent the of transcripts in tissues other than brain, although at lower The to and although of this may have been to the in which a of in the of and to a of to in the of the or to the in the The tissues that the most abundant level of NCKX3 brain, were rich in smooth as aorta, uterus, and Many other tissues expressed lower levels, but and to for of expression more that of than of the other family members, which are thought to have expression NCKX1 in in and and in and muscle. The of NCKX3 in cell of the or has to have been no of K+-dependent Na+/Ca2+ exchange activity in these tissues or cell present the of the expression for Na+/Ca2+ exchanger family members are The in brain, at least four Na+/Ca2+ exchanger NCKX2, and are present at high levels, that of tissues or cell with or in the of these exchangers, important The in transport and an for exchangers to Ca2+ homeostasis in the the membrane are lower than this to the expression of NCKX1 in rod may in other role for exchanger in the transport of of Ca2+ M. M. M. S. 2000; PubMed Scopus Google Scholar). We have not NCKX3 transport that NCKX3 activity although these no significant on the of or and J. that more with the transport of than with the of other family to the of for the Na+/Ca2+ exchanger family members the of of The of an for of Na+/Ca2+ exchangers, M. J. PubMed Scopus Google and A. S. A. S. Y. S. Y. M. Y. Y. J. 2000; PubMed Scopus (180) Google in this but are by the of the sequence in which a for of this have the and characterization of a a member of the family of K+-dependent the other two members, rod NCKX1 and cone/neuronal NCKX2, NCKX3 K+-dependent activity when with the with ion or with not with Na+ and an for of the functional NCKX3 with in the as also on the of transport. with the high of amino acid sequence similarity to which has been to transport Na+ in exchange for K+ and PubMed Scopus Google P.P.M. J. Physiol. PubMed Google that NCKX3 has a with the the regions of the in the pocket for ion D.A. M. Y. K.D. J. 1999; PubMed Scopus Google D.A. Matsuoka S. K.D. J. PubMed Scopus Google Scholar). on a of NCKX1 and a have regions also the transport for K+-dependent P.P.M. J. 2000; PubMed Scopus Google Scholar). of the sequences NCKX3 and these the high sequence similarity anticipated within the NCKX3 more in these regions than the these of to or with NCKX3 in to and thus this sequence on the amino acids to to the of the K+-dependent class of Na+/Ca2+ as as in a for NCKX3 that to previously for other family members The NCKX3 protein with a functionally region that may a in a to that for M. Nicoll D.A. K.D. M. 1995; PubMed Scopus Google J. 1995; PubMed Scopus Google J. J. 1995; PubMed Scopus Google Scholar). The of this region in the expressed protein the level of functional expression of NCKX3 K+-dependent Na+/Ca2+ exchange activity when assayed using fura-2 digital the expressed activity in in and not a significant in the of protein expression, the NCKX3 protein the N-terminal hydrophobic sequence may or to the membrane more than the protein this sequence. The NCKX3 protein of a extracellular at the by a of a and a of hydrophobic The which to on a to NCKX1 and sequences for protein using of have that the hydrophobic region of that of four and a that the membrane D.A. M. Y. K.D. J. 1999; PubMed Scopus Google A. M. J. 2000; PubMed Scopus Google Y. A. M. 1999; PubMed Scopus Google Scholar). of NCKX3 suggests a with the from the protein which on the extracellular of the The of a and the that the K+-dependent Na+/Ca2+ exchangers may have a from of the to The for NCKX3 are in and in sequence on in The two of the NCKX3 are the which the especially the are the of in to the of other Na+/Ca2+ exchanger The NCKX1 share an that from the the by also see A. PubMed Scopus Google Scholar and P.P.M. PubMed Scopus Google Scholar). the sequence of NCKX3 the of the hydrophobic for NCKX3 and from the NCKX1 and or the distinct and the sequence similarity within the NCKX3 have in a and from other and family The of expression of NCKX3 transcripts in tissues in and by and in by these that NCKX3 most expressed in various in more detail in of using in which a The highest levels of NCKX3 were found in in distinct of the by the CA1 of the and of layer from of and in M. J. J. Scopus Google J. PubMed Scopus Google Scholar). for of these exchangers were also abundant in but the for All three exchangers were present in hippocampal but NCKX3 in CA1 the exchanger a NCKX3 and expression in the NCKX3 from the and from the nuclei, of NCKX3 expression in to other K+-dependent the of transcripts in tissues other than brain, although at lower The to and although of this may have been to the in which a of in the of and to a of to in the of the or to the in the The tissues that the most abundant level of NCKX3 brain, were rich in smooth as aorta, uterus, and Many other tissues expressed lower levels, but and to for of expression more that of than of the other family members, which are thought to have expression NCKX1 in in and and in and muscle. The of NCKX3 in cell of the or has to have been no of K+-dependent Na+/Ca2+ exchange activity in these tissues or cell present the of the expression for Na+/Ca2+ exchanger family members are The in brain, at least four Na+/Ca2+ exchanger NCKX2, and are present at high levels, that of tissues or cell with or in the of these exchangers, important The in transport and an for exchangers to Ca2+ homeostasis in the the membrane are lower than this to the expression of NCKX1 in rod may in other role for exchanger in the transport of of Ca2+ M. M. M. S. 2000; PubMed Scopus Google Scholar). We have not NCKX3 transport that NCKX3 activity although these no significant on the of or and J. that more with the transport of than with the of other family The to the of for the Na+/Ca2+ exchanger family members the of of The of an for of Na+/Ca2+ exchangers, M. J. PubMed Scopus Google and A. S. A. S. Y. S. Y. M. Y. Y. J. 2000; PubMed Scopus (180) Google in this but are by the of the sequence in which a for of We and of for of and and of for in of expression A. of for and the of for of these of a member of the exchanger of

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