Lithium-calcium exchange is mediated by a distinct potassium-independent sodium-calcium exchanger.
Sodium-calcium exchangers have long been considered inert with respect to monovalent cations such as lithium, choline, and N-methyl-d-glucamine. A key question that has remained unsolved is how despite this, Li(+) catalyzes calcium exchange in mammalian tissues. Here we report that a Na(+)/Ca(2+) exchanger, NCLX cloned from human cells (known as FLJ22233), is distinct from both known forms of the exchanger, NCX and NCKX in structure and kinetics. Surprisingly, NCLX catalyzes active Li(+)/Ca(2+) exchange, thereby explaining the exchange of these ions in mammalian tissues. The NCLX protein, detected as both 70- and 55-KDa polypeptides, is highly expressed in rat pancreas, skeletal muscle, and stomach. We demonstrate, moreover, that NCLX is a K(+)-independent exchanger that catalyzes Ca(2+) flux at a rate comparable with NCX1 but without promoting Na(+)/Ba(2+) exchange. The activity of NCLX is strongly inhibited by zinc, although it does not transport this cation. NCLX activity is only partially inhibited by the NCX inhibitor, KB-R7943. Our results provide a cogent explanation for a fundamental question. How can Li(+) promote Ca(2+) exchange whereas the known exchangers are inert to Li(+) ions? Identification of this novel member of the Na(+)/Ca(2+) superfamily, with distinct characteristics, including the ability to transport Li(+), may provide an explanation for this phenomenon.
Palty
Raz
R
Department of Physiology, Faculty of Health Sciences, The National Institute for Molecular Biology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Ohana
Ehud
E
Hershfinkel
Michal
M
Volokita
Micha
M
Elgazar
Vered
V
Beharier
Ofer
O
Silverman
William F
WF
Argaman
Miriam
M
Sekler
Israel
I
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D017136:Ion Transport; D008094:Lithium / Q000378:metabolism*; D008969:Molecular Sequence Data; D011188:Potassium / Q000378:metabolism*; D020033:Protein Isoforms; D019831:Sodium-Calcium Exchanger / Q000032:analysis / Q000737:chemistry / Q000502:physiology*
D020033:Protein Isoforms; D019831:Sodium-Calcium Exchanger; D008094:Lithium; D011188:Potassium; D002118:Calcium