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J. Biol. Chem., Vol. 279, Issue 39, 40634-40639, September 24, 2004

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Ca²+ Controls Functional Expression of the Cardiac K⁺ Transient Outward Current via the Calcineurin Pathway^*

Emeline Perrier, Romain Perrier, Sylvain Richard, and Jean-Pierre Bénitah

From the INSERM U637, CHU A. de Villeneuve, 34295 Montpellier, France

The transient outward K⁺ current (I_to) modulates transmembrane Ca²⁺ influx into cardiomyocytes, which, in turn, might act on I_to. Here, we investigated whether Ca²⁺ modifies functional expression of I_to. Whole-cell I_to were recorded using the patch clamp technique in single right ventricular myocytes isolated from adult rats and incubated for 24 h at 37 °C in a serum-free medium containing various Ca²⁺ concentrations ([Ca²⁺]_o). Increasing the [Ca²⁺]_o from 0.5 to 1.0 and 2.5 mM produced a gradual decrease in I_to density without change in current kinetics. Quantitativereverse transcriptase-PCR showed that a decrease of the Kv4.2 mRNA could account for this decrease. In the acetoxymethyl ester form of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM)-loaded myocytes (a permeant Ca²⁺ chelator), I_to density increased significantly when cells were exposed for 24 h to either 1 or 2.5 mM [Ca²⁺]_o. Moreover, 24-h exposure to the Ca²⁺ channel agonist, Bay K8644, in 1 mM [Ca²⁺]_o induced a decrease in I_to density, whereas the Ca²⁺ channel antagonist, nifedipine, blunted I_to decrease in 2.5 mM [Ca²⁺]_o. The decrease of I_to in 2.5 mM [Ca²⁺]_o was also prevented by co-incubation with either the calmodulin inhibitor W7 or the calcineurin inhibitors FK506 or cyclosporin A. Furthermore, in myocytes incubated for 24 h with 2.5 mM [Ca²⁺]_o, calcineurin activity was significantly increased compared with 1 mM [Ca²⁺]_o. Our data suggest that modulation of [Ca²⁺]_i via L-type Ca²⁺ channels, which appears to involve the Ca²⁺/calmodulin-regulated protein phosphatase calcineurin, down-regulates the functional expression of I_to. This effect might be involved in many physiological and pathological modulations of I_to channel expression in cardiac cells, as well other cell types.

Received for publication, July 6, 2004

^* 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.

To whom correspondence should be addressed: INSERM U637, CHU A. de Villeneuve, 34295 Montpellier, France. Tel.: 33-4-67-41-52-38; Fax: 33-4-67-41-52-42; E-mail: benitah{at}montp.inserm.fr.

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