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Norepinephrine- and epinephrine-induced distinct beta2-adrenoceptor signaling is dictated by GRK2 phosphorylation in cardiomyocytes.

Wang, Y; De Arcangelis, V; Gao, X; Ramani, B; Jung, YS; Xiang, Y
The Journal of biological chemistry, 283(4):1799-1807, 2008
Journal Title
The Journal of biological chemistry
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 beta(2)AR signaling induced by Epi or NE in cardiac tissue. The Epi-activated beta(2)AR induced a rapid contraction rate increase that peaked at 4 min after stimulation. In contrast, the NE-activated beta(2)AR induced a much slower contraction rate increase that peaked at 10 min after stimulation. Whereas both drugs activated beta(2)AR coupling to G(s) proteins, only Epi-activated receptors were capable of coupling to G(i) proteins. Subsequent studies showed that the Epi-activated beta(2)AR 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 beta(2)ARs underwent slow GRK2 phosphorylation, receptor internalization and recycling, and failed to couple to G(i). Moreover, inhibiting beta(2)AR phosphorylation by betaARK C terminus or dephosphorylation by okadaic acid prevented sufficient recycling and G(i) coupling. Together, our data revealed that distinct temporal phosphorylation of beta(2)AR 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 beta(2)AR 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.
MeSH terms
Adrenergic alpha-AgonistsAdrenergic beta-2 Receptor AgonistsAnimalsCells, CulturedEnzyme Inhibitors/pharmacologyEpinephrine/metabolismEpinephrine/pharmacology*G-Protein-Coupled Receptor Kinase 2/metabolism*GTP-Binding Protein alpha Subunits, Gi-Go/metabolismMiceMice, KnockoutMyocardial Contraction/drug effectsMyocardial Contraction/physiologyMyocytes, Cardiac/cytologyMyocytes, Cardiac/metabolism*Norepinephrine/metabolismNorepinephrine/pharmacology*Okadaic Acid/pharmacologyPhosphorylation/drug effects*
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Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
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정, 이숙
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