HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 24, 16505-16513, June 13, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/24/16505    most recent M801424200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Villa-Abrille, M. C. Articles by O'Rourke, B. Search for Related Content PubMed PubMed Citation Articles by Villa-Abrille, M. C. Articles by O'Rourke, B. Social Bookmarking                      What's this?

Insulin Effects on Cardiac Na⁺/Ca²⁺ Exchanger Activity

ROLE OF THE CYTOPLASMIC REGULATORY LOOP^*

From the Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205

Insulin can alter myocardial contractility, in part through an effect on the cardiac sarcolemmal Na⁺/Ca²⁺ exchanger (NCX), but little is known about its mechanism of action. The large cytoplasmic domain (f-loop) of NCX is required for regulation by various intracellular factors, and we have shown previously that residues 562–679 are determinants of NCX inhibition by exchanger inhibitory peptide (XIP). Here we show that the same f-loop deletion eliminates the enhancement of NCX current by insulin, and we examine the signal pathways involved in the insulin response. NCX current (I_NCX) was measured in freshly isolated or cultured (up to 48 h) adult guinea pig myocytes and in myocytes expressing canine NCX1.1 with the 562–679 f-loop deletion (NCX-(562–679)) via adenoviral gene transfer. I_NCX was recorded by whole-cell patch clamp as the Ni²⁺-sensitive current at 37 °C with intracellular Ca²⁺ buffered. Insulin (1 µM) increased I_NCX (at +80 mV) by 110 and 83% in fresh and cultured myocytes, respectively, whereas in myocytes expressing NCX-(562–679) the response was eliminated (with 100 µM XIP included to suppress any native guinea pig I_NCX). The insulin effect on I_NCX was not inhibited by wortmannin, a nitric-oxide synthase inhibitor, or disruption of caveolae but was blocked by chelerythrine, implicating protein kinase C, but not phosphatidylinositol-3-kinase, in the mechanism. The insulin effect was also not additive with phosphatidylinositol-4,5-bisphosphate-induced activation of I_NCX. The finding that the 562–670 f-loop domain is implicated in both XIP and receptor-mediated modulation of NCX highlights its important role in acute physiological or pathophysiological regulation of Ca²⁺ balance in the heart.

Received for publication, February 21, 2008 , and in revised form, March 31, 2008.

^* The work was supported, in whole or in part, by National Institutes of Health Grants R01-HL61711 and P01-HL81427. 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.

¹ To whom correspondence should be addressed: The Johns Hopkins University, Dept. of Medicine, 720 Rutland Ave., 1059 Ross Bldg., Baltimore, MD 21205-2195. E-mail: bor{at}jhmi.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?