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J Biol Chem, Vol. 273, Issue 30, 18819-18825, July 24, 1998

A Novel Molecular Determinant for cAMP-dependent Regulation of the Frog Heart Na⁺-Ca²⁺ Exchanger

Yaroslav M. Shuba, Tomoko Iwata, Valery G. Naidenov, Murat Oz, Katherine Sandberg, Alexander Kraev, Ernesto Carafoli, and Martin Morad

From the Departments of Pharmacology and Medicine, Georgetown University Medical Center, Washington, DC 20007 and  Laboratory of Biochemistry, Swiss Federal Institute of Technology (ETH), Universitatsstrasse 16, CH-8092 Zürich, Switzerland

Na⁺-Ca²⁺ exchanger is one of the major sarcolemmal Ca²⁺ transporters of cardiac myocytes. In frog ventricular myocytes the exchanger is regulated by isoproterenol via a -adrenoreceptor/adenylate-cyclase/cAMPdependent signaling pathway providing a molecular mechanism for the relaxant effect of the hormone. Here, we report on the presence of a novel exon of 27-base pair insertion, which generates a nucleotide binding motif (P-loop) in the frog cardiac Na⁺-Ca²⁺ exchanger. To examine the functional role of this motif, we constructed a full-length frog heart Na⁺-Ca²⁺ exchanger cDNA (fNCX1a) containing this exon. The functional expression of fNCX1a in oocytes showed characteristic voltage dependence, divalent (Ni²⁺, Cd²⁺) inhibition, and sensitivity to cAMP in a manner similar to that of native exchanger in frog myocytes. In oocytes expressing the dog heart NCX1 or the frog mutant (fNCX1a) lacking the 9-amino acid exon, cAMP failed to regulate Na⁺-dependent Ca²⁺ uptake. We suggest that this motif is responsible for the observed cAMP-dependent functional differences between the frog and the mammalian hearts.

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