A novel molecular determinant for cAMP-dependent regulation of the frog heart Na+-Ca2+ exchanger

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Abstract

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 β-adrenoreceptor/adenylate- cyclase/cAMP-dependent 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 (ΔfNCX1a) 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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Shuba, Y. M., Iwata, T., Naidenov, V. G., Oz, M., Sandberg, K., Kraev, A., … Morad, M. (1998). A novel molecular determinant for cAMP-dependent regulation of the frog heart Na+-Ca2+ exchanger. Journal of Biological Chemistry, 273(30), 18819–18825. https://doi.org/10.1074/jbc.273.30.18819

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