The Journal of General Physiology, Vol 105, 403-420, Copyright © 1995 by The Rockefeller University Press

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Regulation of the cardiac Na(+)-Ca2+ exchanger by Ca2+. Mutational analysis of the Ca(2+)-binding domain

S Matsuoka, DA Nicoll, LV Hryshko, DO Levitsky, JN Weiss and KD Philipson
Department of Physiology, University of California, Los Angeles School of Medicine 90095-1760, USA.

The sarcolemmal Na(+)-Ca2+ exchanger is regulated by intracellular Ca2+ at a high affinity Ca2+ binding site separate from the Ca2+ transport site. Previous data have suggested that the Ca2+ regulatory site is located on the large intracellular loop of the Na(+)-Ca2+ exchange protein, and we have identified a high-affinity 45Ca2+ binding domain on this loop (Levitsky, D. O., D. A. Nicoll, and K. D. Philipson. 1994. Journal of Biological Chemistry. 269:22847-22852). We now use electrophysiological and mutational analyses to further define the Ca2+ regulatory site. Wild-type and mutant exchangers were expressed in Xenopus oocytes, and the exchange current was measured using the inside- out giant membrane patch technique. Ca2+ regulation was measured as the stimulation of reverse Na(+)-Ca2+ exchange (intracellular Na+ exchanging for extracellular Ca2+) by intracellular Ca2+. Single-site mutations within two acidic clusters of the Ca2+ binding domain lowered the apparent Ca2+ affinity at the regulatory site from 0.4 to 1.1-1.8 microM. Mutations had parallel effects on the affinity of the exchanger loop for 45Ca2+ binding (Levitsky et al., 1994) and for functional Ca2+ regulation. We conclude that we have identified the functionally important Ca2+ binding domain. All mutant exchangers with decreased apparent affinities at the regulatory Ca2+ binding site also have a complex pattern of altered kinetic properties. The outward current of the wild-type Na(+)-Ca2+ exchanger declines with a half time (th) of 10.8 +/- 3.2 s upon Ca2+ removal, whereas the exchange currents of several mutants decline with th values of 0.7-4.3 s. Likewise, Ca2+ regulation mutants respond more rapidly to Ca2+ application. Study of Ca2+ regulation has previously been possible only with the exchanger operating in the reverse mode as the regulatory Ca2+ and the transported Ca2+ are then on opposite sides of the membrane. The use of exchange mutants with low affinity for Ca2+ at regulatory sites also allows demonstration of secondary Ca2+ regulation with the exchanger in the forward or Ca2+ efflux mode. In addition, we find that the affinity of wild-type and mutant Na(+)-Ca2+ exchangers for intracellular Na+ decreases at low regulatory Ca2+. This suggests that Ca2+ regulation modifies transport properties and does not only control the fraction of exchangers in an active state.
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				T. Iwamoto, A. Uehara, I. Imanaga, and M. Shigekawa The Na+/Ca2+ Exchanger NCX1 Has Oppositely Oriented Reentrant Loop Domains That Contain Conserved Aspartic Acids Whose Mutation Alters Its Apparent Ca2+ Affinity J. Biol. Chem., December 1, 2000; 275(49): 38571 - 38580. [Abstract] [Full Text] [PDF]

				K. Wakimoto, K. Kobayashi, M. Kuro-o, A. Yao, T. Iwamoto, N. Yanaka, S. Kita, A. Nishida, S. Azuma, Y. Toyoda, et al. Targeted Disruption of Na+/Ca2+ Exchanger Gene Leads to Cardiomyocyte Apoptosis and Defects in Heartbeat J. Biol. Chem., November 17, 2000; 275(47): 36991 - 36998. [Abstract] [Full Text] [PDF]

				M. Condrescu and J. P. Reeves Inhibition of Sodium-Calcium Exchange by Ceramide and Sphingosine J. Biol. Chem., February 2, 2001; 276(6): 4046 - 4054. [Abstract] [Full Text] [PDF]

				M. Ottolia, S. John, Z. Qiu, and K. D. Philipson Split Na+-Ca2+ Exchangers. IMPLICATIONS FOR FUNCTION AND EXPRESSION J. Biol. Chem., May 25, 2001; 276(22): 19603 - 19609. [Abstract] [Full Text] [PDF]

				S.-H. Woo and M. Morad Bimodal regulation of Na+-Ca2+ exchanger by beta -adrenergic signaling pathway in shark ventricular myocytes PNAS, February 13, 2001; 98(4): 2023 - 2028. [Abstract] [Full Text] [PDF]

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