G-Protein-Coupled Receptors in Heart Disease

Abstract

GPCRs (G-protein [guanine nucleotide-binding protein]-coupled receptors) play a central physiological role in the regulation of cardiac function in both health and disease and thus represent one of the largest class of surface receptors targeted by drugs. Several antagonists of GPCRs, such as βARs (β-adrenergic receptors) and Ang II (angiotensin II) receptors, are now considered standard of therapy for a wide range of cardiovascular disease, such as hypertension, coronary artery disease, and heart failure. Although the mechanism of action for GPCRs was thought to be largely worked out in the 80s and 90s, recent discoveries have brought to the fore new and previously unappreciated mechanisms for GPCR activation and subsequent downstream signaling. In this review, we focus on GPCRs most relevant to the cardiovascular system and discuss traditional components of GPCR signaling and highlight evolving concepts in the field, such as ligand bias, β-arrestin-mediated signaling, and conformational heterogeneity.

Keywords: GPCR; arrestin; bias; coronary artery disease; heart failure; hypertension.

Figure 1.. Scheme of GPCR signaling.

Upon agonist ligand binding, GPCRs interact with heterotrimeric G proteins. G proteins undergoes a GDP-GTP exchange on the α subunit, leading to the dissociation of the α and βγ subunits and subsequent activation of downstream signaling effectors. G protein-activated PKC and PKA in turn phosphorylates the receptor and turns off the G protein signaling (heterologous desensitization, red line and phosphate). GRK-mediated GPCR phosphorylation leads to the recruitment of β-arrestins, resulting in desensitization by sterically interdicting G protein interaction (homologous desensitization, purple line and phosphate), and subsequent receptor internalization and ubiquitination. β-arrestin engagement with the receptor also initiates the activation of β-arrestin-mediated signaling. PLC: phospholipase C; PIP2: phosphatidylinositol 4,5-bisphosphate; IP3: inositol-1,4,5-trisphosphate; DAG: diacylglycerol; AC: adenylate cyclase; PKA: protein kinase A; PI3K: phosphoinositide 3-kinase; GRK: G protein-coupled receptor kinase; EGFR: epidermal growth factor receptor; MAPK: mitogen-activated protein kinase.

Figure 2.. Modes of GPCR signaling.

A. Biased agonism of GPCRs and potential clinical implications. Biased agonists selectively activate G protein- or β-arrestin-mediated signaling pathways. Allosteric modulators bind to distinct sites on the receptor and modulate the activity of orthosteric ligands in various manners. Previous studies suggest that sustained G protein signaling activated by β₁ARs or AT1Rs is associated with deleterious cardiac effects, while β-arrestin signaling may be beneficial for cardiac function. Therefore, β₁AR and AT1R β-arrestin-biased agonists and allosteric modulators may block the detrimental G protein activation while enhancing the cardioprotective effects. B. Scheme of the main features of GPCR structure involved in downstream signaling. Biophysical studies of a number of GPCRs show how upon stimulation certain regions of the receptor are more prone to move allowing the binding of the effectors. In particular, the release of the ionic lock between TM3 and TM6 is critical for receptor activation; ICL2, ICL3, TM5 and TM6 seem mainly involved in G protein signaling initiation. β-arrestin binds to the receptor in two configurations: interacting with the receptor tail to mediate receptor internalization and β-arrestin signaling, or interacting with the receptor transmembrane core to desensitize G protein signaling.

Figure 3.. Functional roles of GPCRs in the cardiovascular system.

A. Pathophysiological roles of βARs in cardiovascular cells. β₁ARs and β₂ARs are differentially expressed in the cardiovascular system. β₁ARs are the predominant βAR subtype in cardiomyocytes, the activation of which increases cardiac contractility and promotes myocyte hypertrophy. β₂ARs are most abundant in cardiac fibroblasts, endothelial cells and vascular smooth muscle cells, where they play important roles in fibrosis and vasodilation. eNOS: endothelial nitric oxide synthase; NO: nitric oxide; VSMC: vascular smooth muscle cell; MLCK: myosin light-chain kinase. B. Schematic representation of AT1R functions in cardiovascular cell types. AT1Rs regulate a complex array of responses in the cardiovascular system. Chronic AT1R activation promotes hypertrophy, fibrosis and cardiac remodeling. ECM: extracellular matrix; MMP: metalloproteinases. C. Main effects of the other GPCRs. GPCRs participate at different levels in the regulation of cardiovascular pathophysiology. Each receptor class will have differential effects depending on the receptor subtype, cell type and mode of stimulation, thus contributing in diverse ways to a specific phenotype. For specific functional roles of individual receptor subtypes, see Table 1. αAR: α adrenergic receptors; MR: muscarinic receptor; ETRs: endothelin receptor; ARs: adenosine receptor; 5-HT: serotonin receptor; HR: histamine receptor; APJ: apelin receptor; RXFP: relaxin family peptide receptor; VR: vasopressin receptor; S1PR: sphingosine 1-phosphate receptor.