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A more recent version of this article appeared on April 21, 2006
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Papers In Press, published online ahead of print February 16, 2006
J. Biol. Chem, 10.1074/jbc.M511460200
Submitted on October 21, 2005
Accepted on February 16, 2006

Enhancement of the recycling and activation of beta -adrenergic receptor by Rab4 GTPase in cardiac myocytes

Catalin M Filipeanu, Fuguo Zhou, May L Lam, Kenneth E Kerut, William C Claycomb, and Guangyu Wu

Pharmacology, Louisiana State University Health Sciences Center, New Orleans, LA 70112

Corresponding Author: gwu{at}lsuhsc.edu

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 beta-adrenergic receptor (beta-AR) in HL-1 cardiac myocytes in vitro and transgenic mouse hearts in vivo. beta1-AR the predominant subtype of beta-AR in HL-1 cardiac myocytes, is internalized after stimulation with isoproterenol (ISO) and fully recycled at 4 hrs upon ISO removal. Transient expression of Rab4 markedly facilitated recycling of internalized beta-AR to the cell surface and enhanced beta-AR signaling as measured by ISO-stimulated cAMP production. Transgenic overexpression of Rab4 in the mouse myocardium significantly increased the number of beta-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 upregulation of the beta-myosin heavy chain gene. These data provide the first evidence indicating that Rab4 is a rate-limiting factor for the recycling of endogenous beta-AR and augmentation of Rab4-mediated traffic enhances beta-AR function in cardiac myocytes.


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