Functional Selectivity in Adrenergic and Angiotensin Signaling Systems

Abstract

␤-Adrenergic and angiotensin II type 1A receptors are therapeutic targets for the treatment of a number of common human diseases. Pharmacological agents designed as antagonists for these receptors have positively affected the morbidity and mortality of patients with hypertension, heart failure, and renal disease. Antagonism of these receptors, however, may only partially explain the therapeutic benefits of ␤-blockers and angiotensin receptor blockers given the emerging concept of functional selectivity or biased agonism. This new pharmacological paradigm suggests that multiple signaling pathways can be differentially modified by a single ligand-receptor interaction. This review examines the functional selectivity of ␤-adrenergic and angiotensin II type 1A receptors with respect to their ability to signal via both G protein-dependent and G protein-independent mechanisms, with a focus on the multifunctional protein ␤-arrestin. Also highlighted are the concept of "biased signaling" through ␤-arrestin mediated pathways, the affect of ligand/receptor modification on such biased agonism, and the implications of functional selectivity for the development of the next generation of ␤-blockers and angiotensin receptor blockers.

Embracing Bias

“…However, recent reports have identified a new pharmacological paradigm of GPCR signaling, in which β-arrestin-mediated, G-protein-independent signaling pathways are activated after the stimulation by certain biased ligands. 7,8 Conventional antagonists compete with endogenous ligands for binding to the GPCR, resulting in an inactive receptor conformation and inhibition of further G-protein signaling. However, a biased antagonist, or a biased ligand, can cause analogous GPCR inactivation, while simultaneously activating β-arrestindependent, G-protein-independent signaling pathways.…”

“…Specifically, GRK2/3-mediated GPCR phosphorylation leads to receptor internalization and signal termination, whereas GRK5/6-mediated GPCR phosphorylation may promote G-protein-independent β-arrestin-mediated signaling. 7 The biased ligand carvedilol, a β-blocker used extensively for the treatment of cardiovascular disease, is reported to exert β1, β2, and α1 adrenergic receptor blockade, in addition to its putative antioxidant effects. This concept of functional selectivity or biased agonism through β-arrestin-mediated pathways provides a potential explanation for the enhanced therapeutic properties of particular β-blockers, such as carvedilol.…”

Inverse agonism: the classic concept of GPCRs revisited [Review]

“…action, similar to that of beta-blockers [51,52], which inhibit one signaling pathway but do not inhibit the other, the ARB add-on effect might be explained. Indeed, a biased AT1 agonist and allosteric activation of AT1 have been reported [53,54].…”

“…However, when attention first started being paid to the concept of biased agonism around 2007, it was rigorously examined whether ARB displays biased action. This hypothesis could not be proven however (Lefkowitz RJ, personal coummunication) [52]. Overall, accumulating data likely have failed to show the superiority of ARB against ACEi and the benefit of the ARB add-on effect to ACEi in cardiovascular protection [45].…”

Arrestins as signaling modulators: the plot thickens. Focus on “Arrestins 2 and 3 differentially regulate ETA and P2Y2 receptor-mediated cell signaling and migration in arterial smooth muscle”

“…A particularly tantalizing aspect of the arrestin saga concerns the abilities of these proteins to regulate cytoskeletal function by serving as protein scaffolds (7). The first mechanism involves arrestin-medicated recruitment of cofilin.…”