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This Article Full Text Full Text (PDF) All Versions of this Article: 291/3/H1226    most recent 00196.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Dong, H. Articles by Lytton, J. Search for Related Content PubMed PubMed Citation Articles by Dong, H. Articles by Lytton, J.

Novel role for K⁺-dependent Na⁺/Ca²⁺ exchangers in regulation of cytoplasmic free Ca²⁺ and contractility in arterial smooth muscle

¹Division of Gastroenterology, Department of Medicine, University of California, San Diego School of Medicine, San Diego, California; and ²Department of Pharmacology and Therapeutics and ³Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada

Submitted 22 February 2006 ; accepted in final form 4 April 2006

Cytoplasmic free Ca²⁺ ([Ca²⁺]_cyt) is essential for the contraction and relaxation of blood vessels. The role of plasma membrane Na⁺/Ca²⁺ exchange (NCX) activity in the regulation of vascular Ca²⁺ homeostasis was previously ascribed to the NCX1 protein. However, recent studies suggest that a relatively newly discovered K⁺-dependent Na⁺/Ca²⁺ exchanger, NCKX (gene family SLC24), is also present in vascular smooth muscle. The purpose of the present study was to identify the expression and function of NCKX in arteries. mRNA encoding NCKX3 and NCKX4 was demonstrated by RT-PCR and Northern blot in both rat mesenteric and aortic smooth muscle. NCXK3 and NCKX4 proteins were also demonstrated by immunoblot and immunofluorescence. After voltage-gated Ca²⁺ channels, store-operated Ca²⁺ channels, and Na⁺ pump were pharmacologically blocked, when the extracellular Na⁺ was replaced with Li⁺ (0 Na⁺) to induce reverse mode (Ca²⁺ entry) activity of Na⁺/Ca²⁺ exchangers, a large increase in [Ca²⁺]_cyt signal was observed in primary cultured aortic smooth muscle cells. About one-half of this [Ca²⁺]_cyt signal depended on the extracellular K⁺. In addition, after the activity of NCX was inhibited by KB-R7943, Na⁺ replacement-induced Ca²⁺ entry was absolutely dependent on extracellular K⁺. In arterial rings denuded of endothelium, a significant fraction of the phenylephrine-induced and nifedipine-resistant aortic or mesenteric contraction could be prevented by removal of extracellular K⁺. Taken together, these data provide strong evidence for the expression of NCKX proteins in the vascular smooth muscle and their novel role in mediating agonist-stimulated [Ca²⁺]_cyt and thereby vascular tone.

vascular tone; calcium homeostasis; rat aorta

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