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Originally published In Press as doi:10.1074/jbc.M206677200 on July 12, 2002

J. Biol. Chem., Vol. 277, Issue 37, 33957-33962, September 13, 2002
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The Molecular Determinants of Ionic Regulatory Differences between Brain and Kidney Na+/Ca2+ Exchanger (NCX1) Isoforms*

Jeremy DunnDagger §, Chadwick L. Elias, Hoa Dinh Le, Alexander Omelchenko, Larry V. Hryshko||, and Jonathan LyttonDagger **

From the Dagger  Cardiovascular Research Group, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta T2N 4N1, Canada and the  Institute of Cardiovascular Sciences, Department of Physiology, Faculty of Medicine, University of Manitoba, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba R2H 2A6, Canada

The Na+/Ca2+ exchanger gene NCX1 undergoes alternative splicing leading to several isoforms that differ in a small portion of the large cytoplasmic loop. This loop is involved in many regulatory processes of NCX1, including ionic regulation by the transported substrates Na+ and Ca2+. High intracellular Ca2+ can alleviate intracellular Na+-dependent inactivation in exon A (NCX1.4)-containing isoforms but not in those containing the mutually exclusive exon B (NCX1.3). Giant excised patches from Xenopus oocytes expressing various NCX1 constructs were used to examine the specific amino acids responsible for these observed regulatory differences. Using a chimeric approach, the region responsible was narrowed down to the small central part of exon A (IDDEEYEKNKTF). Replacing the second aspartic acid of this sequence with arginine (the corresponding amino acid in exon B) in an exon A background completely prevented the effect of Ca2+ on intracellular Na+-dependent inactivation. Mutating the second lysine to cysteine (exon B) had a similar, but only partial, effect. The converse double mutant, but neither single mutation alone, introduced into an exon B background (arginine to aspartic acid and cysteine to lysine) was able to restore the NCX1.4 regulatory phenotype. These data demonstrate that aspartic acid 610 and lysine 617 (using the rat NCX1.4 numbering scheme) are critical molecular determinants of the unique Ca2+ regulatory properties of NCX1.4.

* This work was supported by operating grants from the Canadian Institutes of Health Research (to J. L. and L. V. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported in part by core funds from a Canadian Institutes of Health research group grant (Wayne Giles, principal investigator) and by a research traineeship from the Heart and Stroke Foundation of Canada.

|| Holds a Canada Research Chair.

** A senior scholar of the Alberta Heritage Foundation for Medical Research and an investigator of the Canadian Institutes of Health Research. To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Calgary Health Sciences Centre, Rm. 2518, 3330 Hospital Dr. NW, Calgary, Alberta T2N 4N1, Canada. Tel.: 403-220-2893; Fax: 403-283-4841; E-mail: jlytton@ucalgary.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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