G protein coupled receptor kinases as therapeutic targets in cardiovascular disease

Abstract

G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors and are responsible for regulating a wide variety of physiological processes. This is accomplished via ligand binding to GPCRs, activating associated heterotrimeric G proteins and intracellular signaling pathways. G protein-coupled receptor kinases (GRKs), in concert with β-arrestins, classically desensitize receptor signal transduction, thus preventing hyperactivation of GPCR second-messenger cascades. As changes in GRK expression have featured prominently in many cardiovascular pathologies, including heart failure, myocardial infarction, hypertension, and cardiac hypertrophy, GRKs have been intensively studied as potential diagnostic or therapeutic targets. Herein, we review our evolving understanding of the role of GRKs in cardiovascular pathophysiology.

Figure 1. G Protein-Coupled Receptor (GPCR) Activation

Generalized schematic for GPCR activation. Upon ligand binding to the GPCR, the receptor undergoes a conformational change whereby the α subunit of its associated G protein is activated by exchanging bound GDP for GTP. The α and βγ subunits of the G protein subsequently dissociate to activate their respective downstream signaling cascades. For a more comprehensive overview of the complex variety of GPCR signaling cascades, please refer to Neves et al.. Abbreviations: PKA, protein kinase A; PYK, protein-rich tyrosine kinase; MEK5, Mitogen/extracellular signal regulated kinase kinase-5; PI3K, phosphatidylinositol-3 kinase; GRK, G protein-coupled receptor kinase; GIRK, G protein-activated inward rectifying K⁺ channel).

Figure 2. GPCR Desensitization

GRKs are recruited to and phosphorylate ligand-occupied GPCRs on the cytoplasmic carboxyl-terminal tail. β-arrestins bind phosphorylated GPCRs with enhanced affinity, thereby creating a platform for: blocking recoupling of the dissociated G-protein subunits to the GPCR, thereby preventing further receptor activation (i.e. desensitization); coordination of GRK and arrestin in assembly of macromolecular signaling complexes; recruitment of endocytotic machinery as a precursor to receptor internalization (i.e. downregulation), whence the receptor may be dephosphorylated and recycled back to the membrane or targeted for lysosomal degradation.

Figure 3. GRK/Gβγ Manipulation

Pictorial representation of putative regulation of GRK/Gβγ functions from recent literature. See text for details.

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