Select G-Protein-Coupled Receptors Modulate Agonist-Induced Signaling via a ROCK, LIMK, and 尾-Arrestin 1 Pathway
文摘
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Summary
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 dorsal root ganglia (DRG) neurons, we find that agonists of delta opioid receptors (未ORs) activate cofilin through Rho-associated coiled-coil-containing protein kinase (ROCK), LIM domain kinase (LIMK), and 尾-arrestin 1 (尾-arr1) to regulate actin polymerization. This controls receptor function,聽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 尾-arr1. Functional evidence of this cascade was demonstrated in聽vivo, where the behavioral effects of 未OR or ORL1 agonists were enhanced in the absence of 尾-arr1 or prevented by inhibiting ROCK. This pathway allows 未OR and ORL1 agonists to rapidly regulate receptor function.