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J. Biol. Chem., Vol. 281, Issue 16, 11097-11103, April 21, 2006

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Enhancement of the Recycling and Activation of -Adrenergic Receptor by Rab4 GTPase in Cardiac Myocytes^*

Catalin M. Filipeanu, Fuguo Zhou, May L. Lam, Kenneth E. Kerut^¶, William C. Claycomb, and Guangyu Wu¹

From the Department of Pharmacology and Experimental Therapeutics, Biochemistry and Molecular Biology and ^¶Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

We investigate the role of Rab4, a Ras-like small GTPase coordinating protein transport from the endosome to the plasma membrane, on the recycling and activation of endogenous -adrenergic receptor (-AR) in HL-1 cardiac myocytes in vitro and transgenic mouse hearts in vivo. ₁-AR, the predominant subtype of -AR in HL-1 cardiac myocytes, was internalized after stimulation with isoproterenol (ISO) and fully recycled at 4 h upon ISO removal. Transient expression of Rab4 markedly facilitated recycling of internalized -AR to the cell surface and enhanced -AR signaling as measured by ISO-stimulated cAMP production. Transgenic overexpression of Rab4 in the mouse myocardium significantly increased the number of -AR in the plasma membrane and augmented cAMP production at the basal level and in response to ISO stimulation. Rab4 overexpression induced concentric cardiac hypertrophy with a moderate increase in ventricle/body weight ratio and posterior wall thickness and a selective up-regulation of the -myosin heavy chain gene. These data provide the first evidence indicating that Rab4 is a rate-limiting factor for the recycling of endogenous -AR and augmentation of Rab4-mediated traffic enhances -AR function in cardiac myocytes.

Received for publication, October 21, 2005 , and in revised form, January 20, 2006.

C. M. F. dedicates this paper to the memory of Dr. Dimitrie Branisteanu.

^* This work was supported in part by National Institutes of Health Award ("Mentoring in Cardiovascular Biology") 1P20RR018766 (program director: Stephen M. Lanier, Ph.D.) and by Louisiana Board of Regents Grant LEQSF (2002-05)-RD-A-18 (to G. W.). 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: Dept. of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112. Tel.: 504-568-2236; Fax: 504-568-2361; E-mail: gwu{at}lsuhsc.edu.

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