Conducting the G-protein Coupled Receptor (GPCR) Signaling Symphony in Cardiovascular Diseases: New Therapeutic Approaches

Abstract

G protein-coupled receptors (GPCRs) are a virtually ubiquitous class of membrane-bound receptors, which functionally couple hormone or neurotransmitter signals to physiological responses. Dysregulation of GPCR signaling contributes to the pathophysiology of a host of cardiovascular disorders. Pharmacological agents targeting GPCRs have been established as therapeutic options for decades. Nevertheless, the persistent burden of cardiovascular diseases necessitates improved treatments. To that end, exciting drug development efforts have begun to focus on novel compounds that discriminately activate particular GPCR signaling pathways.

Figure 1. Generalized Schematic of Conventional and Biased Cardiac β₁-AR Signaling

Epinephrine and norepinephrine enhance myocardial contractility, heart rate, and apoptosis through Gα_s-coupled signaling pathways in heart (black arrows). Furthermore, these catecholamines can activate an anti-apoptotic cascade independent of Gα_s (green arrows). Putative biased ligands induce cardioprotection by exclusively promoting the G protein coupled receptor kinase (GRK) and β-arrestin-mediated pathway (green arrows).

Figure 2. Generalized Schematic of Conventional and Biased AT₁R Signaling

Ang II stimulation of AT₁Rs produces vasoconstriction and augmented contractility in the vasculature and myocardium, respectively (black arrows). Biased ligands (e.g. TRV120027) selectively promote G protein coupled receptor kinase (GRK) and β-arrestin-mediated signaling, thereby enhancing myocardial contractility and reducing vasoconstriction (green arrows).