Intracellular membrane trafficking involves a series of membrane budding and fusion events. These are regulated by specific
cytosolic and membrane-associated protein factors, among which are a group of Ras-like small guanosine triphosphatases
(GTPases) called adenosine diphosphate (ADP)-ribosylation factors (ARFs). These factors were originally identified as cofactors
required for the cholera toxin-catalyzed ADP-ribosylation of Gs, alpha subunit (GNAS1; 139320); see ADP-ribosylation factor-1
(ARF1; 103180). The ARF family consists of 15 structurally related gene products that include 6 ARF proteins and 11 ARF-like
proteins. The ARF proteins are divided into 3 classes on the basis of size and amino acid identity.
NCBI Summary:
This gene encodes a member of the human ARF gene family, which is part of the RAS superfamily. The ARF genes encode small guanine nucleotide-binding proteins that stimulate the ADP-ribosyltransferase activity of cholera toxin and play a role in vesicular trafficking and as activators of phospholipase D. The product of this gene is localized to the plasma membrane, and regulates vesicular trafficking, remodelling of membrane lipids, and signaling pathways that lead to actin remodeling. A pseudogene of this gene is located on chromosome 7. [provided by RefSeq, Jul 2008]
General function
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Follicle development
Comment
Expression regulated by
LH
Comment
Luteinizing hormone/chorionic gonadotrophin receptor overexpressed in granulosa cells from polycystic ovary syndrome ovaries is functionally active. Kanamarlapudi V et al. (2016) Polycystic ovarian syndrome (PCOS) is associated with anovulatory infertility. Luteinizing hormone/chorionic gonadotrophin receptor (LHCGR), which is critical for ovulation, has been suggested to be expressed prematurely in the ovarian follicles of women with PCOS. This study aimed to analyse the expression and activity of LHCGR in ovarian granulosa cells from PCOS patients and the involvement of ARF6 small GTPase in LHCGR internalization. Granulosa cells (GC) isolated from follicular fluid collected during oocyte retrieval from normal women (n = 19) and women with PCOS (n = 17) were used to study differences in LHCGR protein expression and activity between normal and PCOS patients. LHCGR expression is up-regulated in GC from PCOS women. LHCGR in PCOS GC is functionally active, as shown by increased cAMP production upon human gonadotrophin (HCG)-stimulation. Moreover, ARF6 is highly expressed in GC from PCOS patients and HCG-stimulation increases the concentrations of active ARF6. The inhibition of ARF6 activation attenuates HCG-induced LHCGR internalization in both normal and PCOS GC, indicating that there are no alterations in LHCGR internalisation in GC from PCOS. In conclusion, the expression and activation of LHCGR and ARF6 are up-regulated in GC from PCOS women but the mechanism of agonist-induced LHCGR internalization is unaltered.//////////////////
ARF6 activated by the LHCG receptor through the cytohesin family of guanine nucleotide exchange factors mediates the receptor internalisation and signalling. Kanamarlapudi V et al. The Luteinizing Hormone Chorionic Gonadotropin Receptor (LHCGR) is a Gs-coupled GPCR that is essential for the maturation and function of the ovary and testis. LHCGR is internalised following its activation, which regulates the biological responsiveness of the receptor. Previous studies indicated that ADP-ribosylation factor (ARF)6 and its GTP-exchange factor (GEF) cytohesin 2 regulate LHCGR internalisation in follicular membranes. However, the mechanisms by which ARF6 and cytohesin 2 regulate LHCGR internalisation remain incompletely understood. Here we investigated the role of the ARF6 signalling pathway in the internalisation of heterologously expressed human LHCGR (HLHCGR) in intact cells using a combination of pharmacological inhibitors, siRNA and the expression of mutant proteins. We found that human CG (HCG)-induced HLHCGR internalisation, cAMP accumulation and ARF6 activation were inhibited by Gallein (? inhibitor), Wortmannin (PI 3-kinase inhibitor), SecinH3 (cytohesin ARF GEF inhibitor), QS11 (an ARF GAP inhibitor), an ARF6 inhibitory peptide and ARF6 siRNA. However, Dynasore (dynamin inhibitor), the dominant negative mutants of NM23-H1 (dynamin activator) and clathrin, and PBP10 (PtdIns 4,5-P2 binding peptide) inhibited agonist-induced HLHCGR and cAMP accumulation but not ARF6 activation. These results indicate that heterotrimeric G-protein, phosphatidylinositol (PI) 3-kinase (PI3K), cytohesin ARF GEF and ARF GAP function upstream of ARF6 whereas dynamin and clathrin act down stream of ARF6 in the regulation of HCG-induced HLHCGR internalisation and signalling. In conclusion, we have identified the components and molecular details of the ARF6 signalling pathway required for agonist-induced HLHCGR internalisation.
Ovarian localization
Granulosa, Theca, Luteal cells
Comment
Hunzicker-Dunn M, et al 2002 reported that ARF6 is a newly appreciated player in G protein-coupled receptor
Desensitization.
The luteinizing hormone/choriogonadotropin hormone receptor (LH/CG R) signals
to regulate ovulation, corpus luteum formation, and fetal survival during
pregnancy. Agonist binding to the LH/CG R is poorly reversible, emphasizing
the importance of a cellular mechanism to temper signaling by a potentially
persistently active receptor. Like other G protein-coupled receptors (GPCRs),
signaling by this receptor is modulated by its binding of an arrestin. The authors have
identified ADP ribosylation factor 6 (ARF6) as a protein whose activation
state is regulated by the LH/CG R and which functions to regulate the
availability of plasma membrane-docked arrestin 2 to this receptor.