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 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 (G(s)) is dependent on GTP and attributable to binding of beta-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 beta-arrestin from the membrane, making beta-arrestin available for LH/CGR; Arf6 but not Arf1 peptides block beta-arrestin release from the membrane. Thus, LH/CGR appears to activate two membrane delimited signaling cascades via two types of G proteins: heterotrimeric G(s) and small G protein Arf6. Arf6 activation releases docked beta-arrestin necessary for receptor desensitization, providing a feedback mechanism for receptor self-regulation.
Mukherjee
S
S
Department of Cell and Molecular Biology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Gurevich
V V
VV
Jones
J C
JC
Casanova
J E
JE
Frank
S R
SR
Maizels
E T
ET
Bader
M F
MF
Kahn
R A
RA
Palczewski
K
K
Aktories
K
K
Hunzicker-Dunn
M
M
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002474:Cell-Free System; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D005246:Feedback; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000502:physiology*; D006064:Gonadotropins, Equine / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000502:physiology; D007986:Luteinizing Hormone / Q000494:pharmacology*; D006080:Ovarian Follicle / Q000378:metabolism; D010062:Ovulation Induction; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D011974:Receptors, LH / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D013552:Swine; D000071557:beta-Arrestins
D000089982:ADP-Ribosylation Factor 6; D019390:Arrestins; D006063:Chorionic Gonadotropin; D020690:GTPase-Activating Proteins; D006064:Gonadotropins, Equine; D010446:Peptide Fragments; D011974:Receptors, LH; D011993:Recombinant Fusion Proteins; D000071557:beta-Arrestins; C102474:cytohesin-2; D006160:Guanosine Triphosphate; D007986:Luteinizing Hormone; D019205:GTP-Binding Protein alpha Subunits, Gs; D020727:ADP-Ribosylation Factors; C000715349:Arf6 protein, rat; D000262:Adenylyl Cyclases