Differential regulation of the cell-surface targeting and function of β- and α1-adrenergic receptors by Rab1 GTPase in cardiac myocytes

Catalin M. Filipeanu, Fuguo Zhou, Erin K. Fugetta, Guangyu Wu

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

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 β- and α1-ARs in neonatal rat ventricular myocytes. Adenovirus-driven expression of Rab1 into myocytes selectively increased the cell-surface number of α1-AR, but not β-AR, whereas the dominant-negative mutant Rab1N124I significantly reduced the cell-surface expression of β-AR and α1-AR. Brefeldin A inhibited β-AR and α1-AR export and antagonized the Rab1 effect on α1-AR expression. Manipulation of Rab1 function similarly influenced the transport of α1A- and α1B-ARs as well as β1- and β2- ARs. Fluorescent microscopy analysis demonstrated that expression of Rab1N124I and Rab1 small interfering RNA induced a marked accumulation of GFP-tagged β2-AR and α1B-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 α1-AR agonist phenylephrine but not to the β-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 β- and α1-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.

Original languageEnglish (US)
Pages (from-to)1571-1578
Number of pages8
JournalMolecular pharmacology
Volume69
Issue number5
DOIs
StatePublished - May 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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