G protein-coupled receptor kinases in normal and failing myocardium

Abstract

Heart failure (HF) is the end stage of many underlying cardiovascular diseases and is among the leading causes of morbidity and mortality in industrialized countries. One of the striking characteristics of HF is the desensitization of G protein-coupled receptor (GPCR) signaling, particularly the beta-adrenergic receptor (betaAR) system. GPCR desensitization is initiated by phosphorylation by GPCR kinases (GRKs), followed by downregulation and functional uncoupling from their G proteins. In the heart, the major GRK isoforms, GRK2 and GRK5, undergo upregulation due to the heightened sympathetic nervous system activity that is characteristic of HF as catecholamine levels increase in an effort to drive the failing pump. This desensitization leads to the distinctive loss of inotropic reserve and functional capacity of the failing heart. Moreover, GRK2 and GRK5 have an increasing non-GPCR interactome, which may play critical roles in cardiac physiology. In the current review, the canonical GPCR kinase function of GRKs and the novel non-GPCR kinase activity of GRKs, their contribution to the pathogenesis of cardiac hypertrophy and HF, and the possibility of GRKs serving as future drug targets will be discussed.

Figure 1

Linear Diagram of GRK2 and GRK5 displaying the classical tri-domain structure of the GRKs. Important interaction and regulation sites are highlighted, including the RGS domain within the amino-terminus of GRK2, the carboxyl terminal region of GRK2 that includes the βARKct and also the amino-terminal GRK5 polymorphism Q41L, which is important in human HF.

Figure 2

GRK2 (a, b, and c) and GRK5 (d, e, and f) mediated GPCR desensitization. a and d: basal condition. GRK2 is cytosolic and GRK5 constitutively bound to the membrane via binding of its polybasic domain to PIP2. b and e: GPCR activation by agonist (A) causes G protein dissociation into βγ subunits and GTP-bound α subunit, which binds to effectors (E) and activate downstream signal transduction. GRK2 binds to G_βγ and PIP2 and translocates from cytosol to membrane. GRK5, on the other hand, does not need the assistance of G_βγ. c and f: GRKs phosphorylate GPCRs and β-arrestin binds to the complex, sterically blocking the activation of G protein, leading to receptor endocytosis and desensitization. The β-arrestins also induce novel signaling pathways distinct from G proteins through their kinase scaffolding (101).

Figure 3

GRK5 functions as a HDAC kinase. During the stage of pathological hypertrophy that precedes HF, increased signaling activity occurs through GPCRs that couple to Gq. Examples of these GPCRs and their agonists are the αAR (Epinephrine), AT₁R (Angiotensin II), and ET₁R (Endothelin). GRK5 nuclear accumulation is downstream of activated Gq (20). Upon entering the nucleus, via its catalytic domain-located NLS, GRK5 can phosphorylate HDAC5, targeting it for nuclear export and releasing its repression on MEF2, a transcription factor crucial in regulating cardiomyocyte growth.