TY - JOUR
T1 - Select G-Protein-Coupled Receptors Modulate Agonist-Induced Signaling via a ROCK, LIMK, and β-Arrestin 1 Pathway
AU - Mittal, Nitish
AU - Roberts, Kristofer
AU - Pal, Katsuri
AU - Bentolila, Laurent A.
AU - Fultz, Elissa
AU - Minasyan, Ani
AU - Cahill, Catherine
AU - Pradhan, Amynah
AU - Conner, David
AU - DeFea, Kathryn
AU - Evans, Christopher
AU - Walwyn, Wendy
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) grants DA05010 (to C.E. and W.W.), DA30866 (to W.W.), GM066151 (to K.D.), and DA031243 (to A.P.) and the Canadian Institutes of Health Research (to C.C.). N.M., W.W., and A.P. are supported in part by Hatos Scholarships, and N.M. is supported by the Gates Millennium Scholars program. STED confocal laser scanning microscopy was performed on a Leica TCS SP5 STED confocal system at the CNSI Institute (CHE-0722519). Flow cytometry was performed in the UCLA JCCC and CAR Flow Cytometry Core Facility (NIH; CA-16042 and AI-28697). Thanks to the laboratories of Drs. Lefkowitz and Seidman for the β-arrestin1 knockout mice, to Dr. G. Calò for Ro65-6570, and to Dr. T. Hales for critical analysis and editing of the final manuscript.
PY - 2013/11/27
Y1 - 2013/11/27
N2 - 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 Ca2+ 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 invivo, 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
AB - 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 Ca2+ 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 invivo, 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
UR - http://www.scopus.com/inward/record.url?scp=84888439320&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2013.10.015
DO - 10.1016/j.celrep.2013.10.015
M3 - Article
C2 - 24239352
AN - SCOPUS:84888439320
SN - 2211-1247
VL - 5
SP - 1010
EP - 1021
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -