Conducting the G-protein coupled receptor (GPCR) signaling symphony in cardiovascular diseases: New therapeutic approaches

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.

Introduction

Straddling the plasma membrane of cells in nearly every tissue and organ of the human body, G protein-coupled receptors (GPCRs) are a conduit for transmitting signals from the external milieu into intracellular responses. That roughly 30–50% of marketed drugs target GPCRs or GPCR-associated mechanisms strongly attests to their biological and clinical significance [1, 2, 3]. In the cardiovascular system, GPCRs modulate crucial functional parameters such as heart rate, vascular tone, contractility, and blood volume. Abnormal GPCR signaling is a common feature of many chronic cardiovascular pathologies such as hypertension [4], heart failure (HF) [5, 6], and cardiomyopathy [7], thus establishing GPCR-directed pharmaceuticals among the most successful components of the modern pharmacopoeia.

The classical notion of GPCR signaling posited that receptors shuttle between ‘on’ and ‘off’ states in the presence or absence of agonist, respectively [8]. The active state entailed a conformational change in the receptor, allowing association with intracellular heterotrimeric G proteins and activation of downstream effectors. Such a simplified paradigm, however, is inadequate to explain the growing complexity of the GPCR signalosome, which includes receptor desensitization and downregulation, allosteric modulation, partial agonism, and ligand bias [3, 9, 10].

As our understanding of structure–function relationships in GPCR activation continues to evolve, it is enticing to speculate that translational application of this information will produce improved cardiovascular therapeutics. We may have only scratched the surface of this endeavor, considering that approximately 1/3 of nearly 200 cardiac GPCRs are ‘orphans’ [11], and only a small portion of over 800 GPCR family members are targets of extant drugs [12]. Moreover, two of the most important cardiovascular GPCRs, β-adrenergic receptors (β-AR) and angiotensin II type 1 receptors (AT1R), are among the best described examples of biased ligand signaling [10], which may be exploited to produce novel benefit from established targets. In this mini-review, we will discuss current GPCR pharmacotherapy in cardiovascular diseases and introduce promising avenues for future drug development.