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J. Biol. Chem., Vol. 279, Issue 39, 40778-40787, September 24, 2004

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Overexpression of ₂-Adrenergic Receptors cAMP-dependent Protein Kinase Phosphorylates and Modulates Slow Delayed Rectifier Potassium Channels Expressed in Murine Heart

EVIDENCE FOR RECEPTOR/CHANNEL CO-LOCALIZATION^*

Keith W. Dilly, Junko Kurokawa¶, Cecile Terrenoire, Steven Reiken||, W. J. Lederer**, Andrew R. Marks||, and Robert S. Kass

From the Departments of Pharmacology and ^||Physiology and Cellular Biophysics, Center for Molecular Cardiology, College of Physicians & Surgeons, Columbia University, New York, New York 10032 and the ^**Institute of Molecular Cardiology. Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201

The cardiac slow delayed rectifier potassium channel (I_Ks), comprised of (KCNQ1) and (KCNE1) subunits, is regulated by sympathetic nervous stimulation, with activation of -adrenergic receptors PKA phosphorylating I_Ks channels. We examined the effects of ₂-adrenergic receptors (₂-AR) on I_Ks in cardiac ventricular myocytes from transgenic mice expressing fusion proteins of I_Ks subunits and h₂-ARs. KCNQ1 and ₂-ARs were localized to the same subcellular regions, sharing intimate localization within nanometers of each other. In I_Ks/B₂-AR myocytes, I_Ks density was increased, and activation shifted in the hyperpolarizing direction; I_Ks was not further modulated by exposure to isoproterenol, and KCNQ1 was found to be PKA-phosphorylated. Conversely, ₂-AR overexpression did not affect L-type calcium channel current (I_CaL) under basal conditions with I_CaL remaining responsive to cAMP. These data indicate intimate association of KCNQ1 and ₂-ARs and that ₂-AR signaling can modulate the function of I_Ks channels under conditions of increased ₂-AR expression, even in the absence of exogenous -AR agonist.

Received for publication, May 28, 2004 , and in revised form, July 9, 2004.

^* This work was supported by National Institutes of Health Grants RO1 HL44365 (to R. S. K.) and PO1 HL67849 (to R. S. K., A. R. M., and W. J. L.). 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.

These authors contributed equally to this work.

^¶ Supported by the Japan Society for the Promotion of Science.

To whom correspondence should be addressed: Dept. of Pharmacology, College of Physicians & Surgeons of, Columbia University, 630 W. 168th St. PH 7W 318, New York, NY 10032. Tel.: 212-305-7444; Fax: 212-342-2703; E-mail: rsk20{at}columbia.edu.

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