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 Jung, Yang Kevin Xiang

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

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 Gs proteins, only Epi-activated receptors were capable of coupling to Gi 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 Gi coupling. In contrast, the NE-activated β2ARs underwent slow GRK2 phosphorylation, receptor internalization and recycling, and failed to couple to Gi. 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.

Original languageEnglish (US)
Pages (from-to)1799-1807
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number4
DOIs
StatePublished - Jan 25 2008
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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