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–
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 b-arrestins, with divergent functional outcomes. In
addition to these canonical roles, numerous noncanonical activities of GRKs and b-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 b-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.