Select G-Protein-Coupled Receptors Modulate Agonist-Induced Signaling via a ROCK, LIMK, and β-Arrestin 1 Pathway

G-protein-coupled receptors (GPCRs) are typically present in a basal, inactive state but, when bound to an agonist, activate downstream signaling cascades. In studying arrestin regulation of opioid receptors in delta ORsal root ganglia (DRG) neurons, we find that agonists of delta opioid receptors (delta ORs) activate cofilin through Rho-associated coiled-coil-containing protein kinase (ROCK), LIM domain kinase (LIMK), and beta-arrestin 1 (beta-arr1) to regulate actin polymerization. This controls receptor function, as assessed by agonist-induced inhibition of voltage-dependent Ca2+ channels in DRGs. Agonists of opioid-receptor-like receptors (ORL1) similarly influence the function of this receptor through ROCK, LIMK, and beta-arr1. Functional evidence of this cascade was demonstrated in vivo, where the behavioral effects of delta OR or ORL1 agonists were enhanced in the absence of beta-arr1 or prevented by inhibiting ROCK. This pathway allows delta OR and ORL1 agonists to rapidly regulate receptor function.