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 dorsal root ganglia (DRG) neurons, we find that agonists of delta opioid receptors (δORs) activate cofilin through Rho-associated coiled-coil-containing protein kinase (ROCK), LIM domain kinase (LIMK), and β-arrestin 1 (β-arr1) to regulate actin polymerization. This controls receptor function, as assessed by agonist-induced inhibition of voltage-dependent Ca(2+) channels in DRGs. Agonists of opioid-receptor-like receptors (ORL1) similarly influence the function of this receptor through ROCK, LIMK, and β-arr1. Functional evidence of this cascade was demonstrated in vivo, where the behavioral effects of δOR or ORL1 agonists were enhanced in the absence of β-arr1 or prevented by inhibiting ROCK. This pathway allows δOR and ORL1 agonists to rapidly regulate receptor function.
Department of Psychiatry and Biobehavioral Sciences, Stefan Hatos Center for Neuropharmacology, Semel Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Nitish
N
Mittal
Kristofer
K
Roberts
Katsuri
K
Pal
Laurent A
LA
Bentolila
Elissa
E
Fultz
Ani
A
Minasyan
Catherine
C
Cahill
Amynah
A
Pradhan
David
D
Conner
Kathryn
K
DeFea
Christopher
C
Evans
Wendy
W
Walwyn
D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D015220:Calcium Channels; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D005727:Ganglia, Spinal; D054461:Lim Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000188:drug therapy; D018408:Patch-Clamp Techniques; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D054460:rho-Associated Kinases / Q000378:metabolism*; D000094942:Nociceptin Receptor
C000605255:Arrb1 protein, mouse; D019390:Arrestins; D001549:Benzamides; D015220:Calcium Channels; D051338:Cofilin 1; D010879:Piperazines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D054461:Lim Kinases; D054460:rho-Associated Kinases; D010749:Phosphoprotein Phosphatases; C529575:SSH1 protein, mouse; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse