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J. Biol. Chem., Vol. 283, Issue 4, 1799-1807, January 25, 2008

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Norepinephrine- and Epinephrine-induced Distinct β₂-Adrenoceptor Signaling Is Dictated by GRK2 Phosphorylation in Cardiomyocytes^*

Yongyu Wang, Vania De Arcangelis, Xiaoguang Gao, Biswarathan Ramani, Yi-sook Jung¹, and Yang Xiang²

From the Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61822

Agonist-dependent activation of G protein-coupled receptors induces diversified receptor cellular and signaling properties. Norepinephrine (NE) and epinephrine (Epi) are two endogenous ligands that activate adrenoceptor (AR) signals in a variety of physiological stress responses in animals. Here we use cardiomyocyte contraction rate response to analyze the endogenous β₂AR signaling induced by Epi or NE in cardiac tissue. The Epi-activated β₂AR induced a rapid contraction rate increase that peaked at 4 min after stimulation. In contrast, the NE-activated β₂AR induced a much slower contraction rate increase that peaked at 10 min after stimulation. Whereas both drugs activated β₂AR coupling to G_s proteins, only Epi-activated receptors were capable of coupling to G_i proteins. Subsequent studies showed that the Epi-activated β₂AR underwent a rapid phosphorylation by G protein-coupled receptor kinase 2 (GRK2) and subsequent dephosphorylation on serine residues 355 and 356, which was critical for sufficient receptor recycling and G_i coupling. In contrast, the NE-activated β₂ARs underwent slow GRK2 phosphorylation, receptor internalization and recycling, and failed to couple to G_i. Moreover, inhibiting β₂AR phosphorylation by βARK C terminus or dephosphorylation by okadaic acid prevented sufficient recycling and G_i coupling. Together, our data revealed that distinct temporal phosphorylation of β₂AR on serine 355 and 356 by GRK2 plays a critical role for dictating receptor cellular events and signaling properties induced by Epi or NE in cardiomyocytes. This study not only helps us understand the endogenous agonist-dependent β₂AR signaling in animal heart but also offers an example of how G protein-coupled receptor signaling may be finely regulated by GRK in physiological settings.

Received for publication, July 12, 2007 , and in revised form, November 30, 2007.

^* This work is supported by National Institutes of Health R01 HL082846-01. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ Present address: Dept. of Physiology, School of Medicine, and Department of Molecular Science and Technology, Ajou University, Suwon 442-749, Korea.

² To whom correspondence should be addressed: Dept. of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, 523 Burrill Hall, 407 S. Goodwin Ave, Urbana, IL 61822. Tel.: 217-265-9448; Fax: 217-333-1133; E-mail: kevinyx{at}uiuc.edu.

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