Designer Approaches for G Protein-Coupled Receptor Modulation for Cardiovascular Disease

The new horizon for cardiac therapy may lie beneath the surface, with the downstream mediators of G protein-coupled receptor (GPCR) activity. Targeted approaches have shown that receptor activation may be biased toward signaling through G proteins or through GPCR kinases (GRKs) and beta-arrestins, with divergent functional outcomes. In addition to these canonical rotes, numerous noncanonical activities of GRKs and beta-arrestins have been demonstrated to modulate GPCR signaling at all levels of receptor activation and regulation. Further, research continues to identify novel GRK/effector and beta-arrestin/effector complexes with distinct impacts on cardiac function in the normal heart and the diseased heart. Coupled with the identification of once orphan receptors and endogenous ligands with beneficial cardiovascular effects, this expands the repertoire of GPCR targets. Together, this research highlights the potential for focused therapeutic activation of beneficial pathways, with simultaneous exclusion or inhibition of detrimental signaling, and represents a new wave of therapeutic development. (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.