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J Mol Med (2009) 87:455463 DOI 10.1007/s00109-009-0450-7
REVIEW
GRK mythology: G-protein receptor kinases in cardiovascular disease
Gerald W. Dorn II
Received: 18 December 2008 /Revised: 21 January 2009 /Accepted: 26 January 2009 /Published online: 20 February 2009 # Springer-Verlag 2009
Abstract G-protein receptor kinases (GRKs) are indispensable for terminating signaling of G-protein coupled receptors (GPCR) through receptor desensitization and downregulation. Increased neurohormone levels in heart failure and the adverse consequences of constant neurohormonal stimulation suggest an important protective role for mechanisms that desensitize neurohormone receptor responses. For that reason, GRK2, the first GRK identified in the heart, has been extensively studied in heart failure, cardiac hypertrophy, and myocardial infarction. However, our understanding of the roles of GRKs in general, and the differential effects of cardiac receptor phosphorylation by individual cardiac-expressed GRKs, have evolved considerably in the last few years. Here, recent developments are reviewed, with an emphasis on novel GRK functions and signaling pathways.
Keywords G-protein receptor kinases .
Adrenergic receptors . Cell signaling .Myocardial infarction . Heart failure
Introduction
G-protein-coupled receptors (GPCR) are a superfamily of over 1,000 heterotrimeric G-protein coupled/7 transmembrane spanning receptors that transduce cell signals from neurohormones, ions, and sensory stimuli to regulate virtually every aspect of mammalian physiology. Drugs, such as receptor agonists and antagonists, phosphodiesterase
inhibitors, kinase inhibitors, and synthase inhibitors, which modulate or mimic endogenous GPCR signaling events, constitute the largest single class of pharmacotherapeutics. Because pathological activation of adrenergic and angiotensin signaling pathways causes or contributes to heart failure, ischemic heart disease, and hypertension, pharmacological inhibition of beta-adrenergic receptors (AR) and of angiotensin signaling through angiotensin AT1 receptor blockade (ARB) or angiotensin-converting enzyme (ACE) inhibition has become the cornerstone of therapy for these cardiovascular disorders. These receptor antagonists and synthetase inhibitors mimic endogenous desensitization of GPCR signaling via the actions of endogenous G-protein receptor kinases (GRK). Here, we review our evolving understanding of the roles for GRKs in cardiac disorders, focusing upon novel findings in mouse models of cardiovascular disease and recent developments in human genetics.
GRKs, the classical paradigm
The conventional role of GRKs is as the off switch for GPCRs (Fig. 1). Phosphorylation of agonist-occupied receptors by GRKs induces recruitment and binding of -arrestins that displace bound G-proteins, therefore uncoupling receptors from their downstream signaling...