Palty Raz, Ohana Ehud, Hershfinkel Michal, Volokita Micha, Elgazar Vered, Beharier Ofer, Silverman William F, Argaman Miriam, Sekler Israel
Department of Physiology, Faculty of Health Sciences, The National Institute for Molecular Biology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
J Biol Chem. 2004 Jun 11;279(24):25234-40. doi: 10.1074/jbc.M401229200. Epub 2004 Apr 1.
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.
长期以来，钠钙交换体一直被认为对锂、胆碱和N-甲基-D-葡萄糖胺等单价阳离子呈惰性。一个尚未解决的关键问题是，尽管如此，Li(+)如何在哺乳动物组织中催化钙交换。在此我们报告，从人类细胞中克隆的一种钠/钙交换体NCLX（也称为FLJ22233），在结构和动力学方面与已知的两种交换体形式NCX和NCKX均不同。令人惊讶的是，NCLX催化活跃的Li(+)/Ca(2+)交换，从而解释了这些离子在哺乳动物组织中的交换情况。NCLX蛋白以70 kDa和55 kDa两种多肽形式被检测到，在大鼠胰腺、骨骼肌和胃中高度表达。此外，我们证明NCLX是一种不依赖钾离子的交换体，其催化Ca(2+)通量的速率与NCX1相当，但不促进Na(+)/Ba(2+)交换。NCLX的活性受到锌的强烈抑制，尽管它不转运这种阳离子。NCLX的活性仅被NCX抑制剂KB-R7943部分抑制。我们的结果为一个基本问题提供了有说服力的解释。Li(+)如何促进Ca(2+)交换，而已知的交换体对Li(+)离子呈惰性？鉴定这个具有独特特征（包括转运Li(+)的能力）的钠/钙超家族新成员，可能为这一现象提供解释。
