Publications

• Lithium-calcium exchange is mediated by a distinct potassium-independent sodium-calcium exchanger.

  Palty R., Ohana E., Hershfinkel M., Volokita M., Elgazar V., Beharier O., Silverman W.F., Argaman M., Sekler I.

  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+) ... >> More

  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. << Less

  J. Biol. Chem. 279:25234-25240(2004) [PubMed] [EuropePMC]

• Identification of residues that control Li+ versus Na+ dependent Ca2+ exchange at the transport site of the mitochondrial NCLX.

  Roy S., Dey K., Hershfinkel M., Ohana E., Sekler I.

  <h4>Background</h4>The Na⁺/Ca²⁺/Li⁺ exchanger (NCLX) is a member of the Na⁺/Ca²⁺ exchanger family. NCLX is unique in its capacity to transport both Na⁺ and Li⁺, unlike other members, which are Na⁺ selective. Th ... >> More

  <h4>Background</h4>The Na⁺/Ca²⁺/Li⁺ exchanger (NCLX) is a member of the Na⁺/Ca²⁺ exchanger family. NCLX is unique in its capacity to transport both Na⁺ and Li⁺, unlike other members, which are Na⁺ selective. The major aim of this study was twofold, i.e., to identify NCLX residues that confer Li⁺ or Na⁺ selective Ca²⁺ transport and map their putative location on NCLX cation transport site.<h4>Method</h4>We combined molecular modeling to map transport site of NCLX with euryarchaeal H⁺/Ca²⁺ exchanger, CAX_Af, and fluorescence analysis to monitor Li⁺ versus Na⁺ dependent mitochondrial Ca²⁺ efflux of transport site mutants of NCLX in permeabilized cells.<h4>Result</h4>Mutation of Asn149, Pro152, Asp153, Gly176, Asn467, Ser468, Gly494 and Asn498 partially or strongly abolished mitochondrial Ca²⁺ exchange activity in intact cells. In permeabilized cells, N149A, P152A, D153A, N467Q, S468T and G494S demonstrated normal Li⁺/Ca²⁺ exchange activity but a reduced Na⁺/Ca²⁺ exchange activity. On the other hand, D471A showed dramatically reduced Li⁺/Ca²⁺ exchange, but Na⁺/Ca²⁺ exchange activity was unaffected. Finally, simultaneous mutation of four putative Ca²⁺ binding residues was required to completely abolish both Na⁺/Ca²⁺ and Li⁺/Ca²⁺ exchange activities.<h4>Conclusions</h4>We identified distinct Na⁺ and Li⁺ selective residues in the NCLX transport site. We propose that functional segregation in Li⁺ and Na⁺ sites reflects the functional properties of NCLX required for Ca²⁺ exchange under the unique membrane potential and ion gradient across the inner mitochondrial membrane.<h4>General significance</h4>The results of this study provide functional insights into the unique Li⁺ and Na⁺ selectivity of the mitochondrial exchanger. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech. << Less

  Biochim. Biophys. Acta 1864:997-1008(2017) [PubMed] [EuropePMC]