Designer Approaches for GPCR Modulation for Cardiovascular Disease.pdf

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