GPCRs in cardiovascular pathologiesConducting the G-protein coupled receptor (GPCR) signaling symphony in cardiovascular diseases: New therapeutic approaches
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.
Section snippets
β-Adrenergic receptors
Whether the underlying pathophysiology is weakened heart muscle secondary to myocardial infarction, or increased afterload as in hypertension or HF, pharmacological inhibition of β-ARs has proven a remarkably successful treatment strategy for a host of cardiovascular indications over the past five decades [13]. The biological effect produced by ‘β-blockers’, eponymously named for their mechanism of action, primarily depends on receptor tissue distribution as well as drug-receptor subtype
Angiotensin II receptors
The other major cardiovascular GPCR that is effectively targeted by modern pharmacology is the AT1R. As the primary effector hormone of the renin–angiotensin–aldosterone system (RAAS), angiotensin II (Ang II) regulates blood pressure by controlling salt and water homeostasis, aldosterone secretion, and vasoconstriction [45]. Ang II receptors are found on a variety of cell types, including cardiac myocytes and fibroblasts, coronary artery and vascular smooth muscle cells, and endothelial cells [
Conclusion
Many of the successes in the annals of drug development involve agents targeting cardiovascular GPCRs (Table 1). In particular, drugs directed at β-AR or AT1R signaling remain standards of treatment for a host of heart maladies. However, cardiovascular diseases continue to impose enormous health and financial burdens. The next advance in treatment may well emerge from our evolving comprehension of ligand–receptor interactions, along with their associated downstream effectors and divergent
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