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Review
. 2016 Aug:110:52-64.
doi: 10.1016/j.phrs.2016.05.008. Epub 2016 May 12.

The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development

Jonathan Hullmann  1 , Christopher J Traynham  2 , Ryan C Coleman  2 , Walter J Koch  3
Affiliations
Review

The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development

Jonathan Hullmann et al. Pharmacol Res. 2016 Aug.

Abstract

Heart failure (HF) is a global epidemic with the highest degree of mortality and morbidity of any disease presently studied. G protein-coupled receptors (GPCRs) are prominent regulators of cardiovascular function. Activated GPCRs are "turned off" by GPCR kinases (GRKs) in a process known as "desensitization". GRKs 2 and 5 are highly expressed in the heart, and known to be upregulated in HF. Over the last 20 years, both GRK2 and GRK5 have been demonstrated to be critical mediators of the molecular alterations that occur in the failing heart. In the present review, we will highlight recent findings that further characterize "non-canonical" GRK signaling observed in HF. Further, we will also present potential therapeutic strategies (i.e. small molecule inhibition, microRNAs, gene therapy) that may have potential in combating the deleterious effects of GRKs in HF.

Keywords: G protein-coupled receptor; G protein-coupled receptor kinase; Heart failure; Hypertrophy; Myocardium.

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Figures

Figure 1
Figure 1. Classical GPCR signaling
Upon ligand binding (blue sphere), GPCRs undergo a conformational change allowing exchange of GDP for GTP on the G protein α subunit (Gα) which in turns activates Gα subunit. Gα and Gβγ subunits dissociate leading to downstream signaling. The agonist occupied receptor is then phosphorylated by a GRK which leads to a conformational change in the receptor and in turn provides a binding site for β-arrestin. β-arrestin binding initiates the recruitment of clathrin and AP-2 which are responsible for catalyzing the endocytosis of the receptor. Following endocytosis, the receptor either undergoes proteasomal degradation or is recycled and trafficked back to the cell membrane. Meanwhile, GTP is hydrolyzed to GDP terminating Gα signaling.
Figure 2
Figure 2. Topology of GRK2, βARKct and GRK5
Classic tri-domain structure of GRK2 and GRK5 contains similar N-terminal regions which interact with activated GPCRs. N-terminal region includes calmodulin (CaM) binding domain (orange) and regulator of G protein signaling (RGS) homology (RH) domain (pink). Interrupting the RH domain is the centrally located kinase domain (blue) with catalytic lysine residue (red). GRK5 differs from GRK2 in that it contains both a nuclear export sequence (NES, tan) and nuclear localization sequence (NLS, green). C-terminus of GRK2 and GRK5 differ in that GRK2 contains a pleckstrin homology (PH) domain (purple) which binds Gβγ. GRK5 lacks this domain; however, contains a second CaM binding domain and amphipathic helix (brown) which allows for membrane association. Also shown is βARKct which is identical to the 194 residue C-terminus of GRK2.
Figure 3
Figure 3. Downregulation of GPCR signaling by GRK2 and restoration of signaling following GRK2 inhibition with βARKct
(A) Upregulation of GRK2, as seen in human heart failure, results in decreased GPCR density and signaling due to desensitization and downregulation of GPCRs at the cell membrane. (B) GRK2 inhibition by βARKct increases GPCR density at the cell membrane and restores receptor signaling responsiveness.
Figure 4
Figure 4. Negative effects of GRK2 upregulation
Upregulation of GRK2, which occurs in human heart failure, results in adrenergic desensitization. (A) β1 adrenergic receptors are downregulated in the heart leading to decreased sympathetic responsiveness and consequently decreased inotropic reserve. (B) Within the vascular smooth muscle, β2 adrenergic receptors are downregulated by GRK2 leading to increased vascular tone. This in turn increases afterload on the heart. (C) Within the adrenal medulla, chromaffin cell α2 adrenergic receptors are downregulated by GRK2 leading to altered feedback inhibition of the sympathetic nervous system and ultimately increased adrenal catecholamine release. This augmented catecholamine release perpetuates the cycle of GRK2 upregulation and impaired β adrenergic receptor responsiveness. Additionally, the upregulated sympathetic activity results in increased vascular tone as well as cardiomyocytes apoptosis. (D) Following ischemia reperfusion injury (I/R), GRK2 phosphorylates eNOS leading to decreased catalytic activity which results in increased cardiomyocyte apoptosis. (E) Additionally, I/R stimulates GRK2 translocation to the mitochondria of cardiomyocytes resulting in altered metabolism and increased ROS production. These detrimental effects within the mitochondria augment cardiomyocytes apoptosis.
Figure 5
Figure 5. Schematic Depicting the Facilitation of Hypertrophic Transcription by GRK5
Nuclear translocation of GRK5 occurs via stimulation of the Gαq pathway following pathologic stimulus such as transaortic constriction (TAC) or phenylephrine (PE) stimulation. This occurs following activation of calmodulin (CaM) by calcium (Ca2+) and subsequent binding to the N-terminus of GRK5. CaM binding causes GRK5 to dissociate from the plasma membrane and translocate to the nucleus. Once in the nucleus, GRK5 phosphorylates HDAC5 leading to its nuclear export and derepression of the transcription factor MEF2. In parallel, CaM also binds to and activates the phosphatase calcineurin which dephosphorylates NFAT leading to its nuclear translocation. At the level of the DNA, GRK5 potentiates NFAT:DNA binding and enhances the transcription of hypertrophic genes and subsequent maladaptive cardiac hypertrophy. Adapted from Hullmann et. al. “GRK5-Mediated Exacerbation of Pathological Cardiac Hypertrophy Involves Facilitation of Nuclear NFAT Activity”, Circ Res (2014) [99].
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