The ADP ribosylation factor nucleotide exchange factor ARNO promotes beta-arrestin release necessary for luteinizing hormone/choriogonadotropin receptor desensitization

Desensitization of guanine nucleotide binding protein-coupled receptors is a ubiquitous phenomenon characterized by declining effector activity upon p ersistent agonist stimulation. The luteinizing hormone/choriogonadotropin r eceptor (LH/CGR) in ovarian follicles exhibits desensitization of effector adenylyl cyclase activity in response to the mid-cycle surge of LH, We have previously shown that uncoupling of the agonist-activated LH/CGR from the stimulatory G protein (G(s)) is dependent on GTP and attributable to bindin g of beta-arrestin present in adenylyl cyclase-rich follicular membrane fra ction to the third intracellular (3i) loop of the receptor. Here, we report that LH/CGR-dependent desensitization is mimicked by ADP ribosylation fact or nucleotide-binding site opener, a guanine nucleotide exchange factor of the small G proteins ADP ribosylation factors (Arfs) 1 and 6, and blocked b y synthetic N-terminal Arf6 peptide, suggesting that the CTP-dependent step of LH/CGR desensitization is receptor-dependent Arf6 activation. Arf activ ation by GTP and ADP ribosylation factor nucelotide-binding site opener pro motes the release of docked beta-arrestin from the membrane, making beta-ar restin available for LH/CGR; Arf6 but not Arf1 peptides block beta-arrestin release from the membrane. Thus, LH/CGR appears to activate two membrane d elimited signaling cascades via two types of C proteins: heterotrimeric G(s ) and small G protein Arf6. Arf6 activation releases docked beta-arrestin n ecessary for receptor desensitization, providing a feedback mechanism for r eceptor self-regulation.