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J. Biol. Chem., Vol. 279, Issue 7, 5867-5876, February 13, 2004

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Molecular Cloning of a Sixth Member of the K⁺-dependent Na⁺/Ca²⁺ Exchanger Gene Family, NCKX6^*

Xinjiang Cai and Jonathan Lytton

From the Cardiovascular Research Group, Department of Biochemistry and Molecular Biology and the Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta T2N 4N1, Canada

Bioinformatic and molecular cloning tools were used to identify and isolate cDNA clones from mouse and human tissues that encode the sixth member of the K⁺-dependent Na⁺/Ca²⁺ exchanger family, NCKX6. The mouse NCKX6 protein is 585 amino acids long and shares about 62% sequence similarity with previously identified exchangers in the -repeat regions but has little primary sequence similarity outside these regions. NCKX6 transcripts of 4 kb are abundantly expressed in all tissues examined and are thus more broadly distributed than previously described NC(K)X family members. Two alternatively spliced products of this novel gene were identified that encode proteins of different length. The short isoform differs from the full-length isoform at the C-terminal hydrophobic domain as a result of a shift in the reading frame caused by the deletion of two exons. Both NCKX6 isoforms were expressed in HEK-293 cells. Functional analysis by digital imaging of fura-2 loaded transfected HEK-293 cells demonstrated that the short isoform exhibited K⁺-dependent Na⁺/Ca²⁺ exchange activity whereas the full-length isoform did not. The latter was retained within the endoplasmic reticulum, whereas the short isoform was present at the plasma membrane in transfected cells. Immunofluorescence studies examining NCKX6 expression in native tissue using an NCKX6-specific antibody showed intense labeling of the cardiac sarcolemmal membrane. The discovery of NCKX6 therefore reveals a novel member of the Na⁺/Ca²⁺ exchanger superfamily whose ubiquitous expression in all tissues suggests an important role for K⁺-dependent Na⁺/Ca²⁺ exchange in maintaining cellular Ca²⁺ homeostasis in diverse tissues and cell types.

Received for publication, October 3, 2003 , and in revised form, November 14, 2003.

^* This work was supported in part by grants from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research. The costs of publication of this article were defrayed in part by the payment of page charges. This 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 a studentship from the Alberta Heritage Foundation for Medical Research.

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{at}ucalgary.ca.

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