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

By Sutapa Mukherjee, Vsevolod V. Gurevich, Jonathan C. R. Jones, James E. Casanova, Scott R. Frank, Evelyn T. Maizels, Marie-France Bader, Richard A. Kahn, Krzysztof Palczewski, Klaus Aktories and Mary Hunzicker-Dunn

Abstract

Desensitization of guanine nucleotide binding protein-coupled receptors is a ubiquitous phenomenon characterized by declining effector activity upon persistent agonist stimulation. The luteinizing hormone/choriogonadotropin receptor (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 (Gs) is dependent on GTP and attributable to binding of β-arrestin present in adenylyl cyclase-rich follicular membrane fraction to the third intracellular (3i) loop of the receptor. Here, we report that LH/CGR-dependent desensitization is mimicked by ADP ribosylation factor nucleotide-binding site opener, a guanine nucleotide exchange factor of the small G proteins ADP ribosylation factors (Arfs) 1 and 6, and blocked by synthetic N-terminal Arf6 peptide, suggesting that the GTP-dependent step of LH/CGR desensitization is receptor-dependent Arf6 activation. Arf activation by GTP and ADP ribosylation factor nucelotide-binding site opener promotes the release of docked β-arrestin from the membrane, making β-arrestin available for LH/CGR; Arf6 but not Arf1 peptides block β-arrestin release from the membrane. Thus, LH/CGR appears to activate two membrane delimited signaling cascades via two types of G proteins: heterotrimeric Gs and small G protein Arf6. Arf6 activation releases docked β-arrestin necessary for receptor desensitization, providing a feedback mechanism for receptor self-regulation

Topics: Biological Sciences
Publisher: The National Academy of Sciences
Year: 2000
OAI identifier: oai:pubmedcentral.nih.gov:18531
Provided by: PubMed Central
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