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Differential Regulation of the Cell-Surface Targeting and Function of - and ₁-Adrenergic Receptors by Rab1 GTPase in Cardiac Myocytes

Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana

The molecular mechanism underlying the export from the endoplasmic reticulum (ER) to the cell surface and its role in the regulation of signaling of adrenergic receptors (ARs) remain largely unknown. In this report, we determined the role of Rab1, a Ras-like GTPase that coordinates protein transport specifically from the ER to the Golgi, in the cell surface targeting and function of endogenous - and ₁-ARs in neonatal rat ventricular myocytes. Adenovirus-driven expression of Rab1 into myocytes selectively increased the cell-surface number of ₁-AR, but not -AR, whereas the dominant-negative mutant Rab1N124I significantly reduced the cell-surface expression of -AR and ₁-AR. Brefeldin A inhibited -AR and ₁-AR export and antagonized the Rab1 effect on ₁-AR expression. Manipulation of Rab1 function similarly influenced the transport of _1A- and _1B-ARs as well as ₁- and ₂-ARs. Fluorescent microscopy analysis demonstrated that expression of Rab1N124I and Rab1 small interfering RNA induced a marked accumulation of GFP-tagged ₂-AR and _1B-AR in the ER. Consistent with the effects on receptor cell-surface targeting, Rab1 selectively enhanced ERK1/2 activation and hypertrophic growth in response to the ₁-AR agonist phenylephrine but not to the -AR agonist isoproterenol. Rab1N124I inhibited both agonist-mediated ERK1/2 activation and hypertrophic growth in neonatal myocytes. These results demonstrate that the cell-surface targeting and signaling of - and ₁-ARs require Rab1 and are differentially modulated by augmentation of Rab1 function. Our data provide strong evidence implicating the ER-to-Golgi traffic as a site for selective manipulation of distinct AR function in cardiac myocytes.

Address correspondence to: Dr. Guangyu Wu, Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112. E-mail: gwu{at}lsuhsc.edu

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