The tail of the gonadotrophin-releasing hormone receptor: desensitization at, and distal to, G protein-coupled receptors
Section snippets
Desensitization and cycling of GPCRs
G protein-coupled receptors (GCPRs), the largest known class of signaling proteins, are characterized structurally by the presence of seven trans-membrane domains, linked by a series of intracellular and extracellular loops. They mediate responses to a vast array of extracellular stimuli ranging from photons, amines, and lipids to peptides and proteins, and are currently major targets for therapeutic interventions. Following agonist binding, GPCRs act as guanine nucleotide exchange factors for
GnRH receptors and effectors
GnRH is a hypothalamic decapeptide which acts via GPCRs on gonadotrophs to stimulate the exocytotic secretion of luteinizing hormone and follicle-stimulating hormone. Agonist occupancy of GnRH receptors activates one or more isoforms of PLC, which hydrolyze membrane phosphoinositides. Hydrolysis of the minor membrane phospholipid, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) yields both diacylglycerol and Ins(1,4,5)P3 which activate most isoforms of protein kinase C (PKC) and mobilize
Do mammalian GnRH receptors undergo rapid homologous desensitization?
Although rapid receptor desensitization (through phosphorylation) is a generally accepted mechanism for GPCR regulation, it has proven technically difficult to demonstrate unambiguously that effects at the receptor level underlie desensitization of PLC-activating GPCRs (Wojcikiewicz et al., 1993) because factors other than receptor desensitization can influence the kinetics of [3H]IPx and Ins(1,4,5)P3 responses. Positive feedback effects of Ca2+ on PLC could conceivably lead to maintenance of
Is the lack of desensitization of mammalian GnRH receptors a result of the lack of required sites for phosphorylation in the C-terminal tail?
The obvious test for whether the lack of mammalian GnRH receptor desensitization is a result of the absence of a C-terminal tail would be to make chimeric receptors containing the GnRH receptor and the C-terminal tail of another GPCR. However, interpretation may be difficult as there is no guarantee that the added tail will adopt an appropriate structure and perform its appropriate function in this environment. It therefore created considerable interest when the first non-mammalian GnRH
What mechanisms of desensitization operate distal to the GnRH receptor?
It has long been known that GnRH-stimulated gonadotrophin secretion desensitizes during sustained stimulation of gonadotrophs with GnRH. The multiple mechanisms contributing towards this effect include depletion of intracellular gonadotrophin pools, internalization of GnRH receptors and GnRH receptor down-regulation. However, because these can be uncoupled from desensitization of gonadotrophin secretion (Jinnah and Conn, 1985, Jinnah and Conn, 1986, McArdle et al., 1987, Conn et al., 1987) and
Summary and directions
Mammalian GnRH receptors are unique. They are the smallest known GPCRs, the only PLC-coupled GPCRs known to lack C-terminal tails and the only PLC-activating GPCRs known not to undergo agonist-induced phosphorylation and desensitization. These features are in stark contrast to those of the non-mammalian GnRH receptors, and indeed to the vast majority of GPCRs including those of yeast. The implication is that these receptors have undergone a period of dramatically accelerated molecular evolution
Acknowledgements
This work was supported by Wellcome Trust (054949, 051555, 16895/1.5), the Neuroendocrine Charitable Trust (164,363) and the Special Trustees of the United of Bristol Hospital Trusts (947).
References (63)
Clinical applications of GnRH and its analogues
Trends Endocrinol. Metab.
(1992)- et al.
Phospholipase C-β1 is a GTPase-activating protein for Gq/11, its physiological regulator
Cell
(1992) - et al.
The molecular mechanism of action of gonadotrophin releasing hormone (GnRH) in the pituitary
Rec. Prog. Horm. Res.
(1987) - et al.
Gonadotropin-releasing hormone receptors with intracellular carboxyl-terminal tails undergo acute desensitization of total inositol phosphate production and exhibit accelerated internalization kinetics
J. Biol. Chem.
(1998) - et al.
Signalling mechanisms during the response of pituitary gonadotrophs to GnRH
Rec. Prog. Horm. Res.
(1995) - et al.
Rat gonadotrophin-releasing hormone (GnRH) receptor: tissue expression and hormonal regulation of its mRNA
Biochem. Biophys. Res. Commun.
(1992) A new family of G-protein regulators-the RGS proteins
Curr. Opin. Cell. Biol.
(1997)- et al.
The role of sequestration in G-protein coupled receptor resensitization
J. Biol. Chem.
(1997) - et al.
The substance P receptor, which couples to Gq/11, is a substrate of beta-adrenergic receptor kinase 1 and 2
J. Biol. Chem.
(1993) - et al.
Truncation of the receptor carboxyl terminus impairs agonist-dependent phosphorylation and desensitization of the α1B-adrenergic receptor
J. Biol. Chem.
(1994)
Role of phosphorylation in desensitization of the β-adrenoceptor
Trends Pharmacol. Sci.
Dynamic video imaging of cytosolic Ca2+ in the αT3-1, gonadotrope-derived cell line
Mol. Cell. Neurosci.
Desensitization of gonadotropin-releasing hormone action in αT3-1 cells due to uncoupling of inositol 1, 4, 5-triphosphate generation and Ca2+ mobilization
J. Biol. Chem.
Phosphorylation is not required for dynamin-dependent endocytosis of a truncated mutant opioid receptor
J. Biol. Chem.
Epitope-tagged gonadotropin-releasing hormone receptors heterologously expressed in mammalian (COS-1) and insect (Sf9) cells
Mol. Cell. Endocrinol.
Expression and signal-transduction pathways of gonadotropin-releasing hormone receptors
Rec. Prog. Horm. Res.
Rapid agonist-mediated phosphorylation of M3-muscarinic receptors revealed by immunoprecipitation
J. Biol. Chem.
Local Ca2+ release from internal stores controls exocytosis in pituitary gonadotrophs
Neuron
Chronic muscarinic stimulation of SH-SY5Y neuoblastoma cells suppresses inositol 1,4,5-trisphosphate action: parallel inhibition of inositol 1,4,5-trisphosphate-induced Ca2+ mobilization and inositol 1,4,5-trisphosphate binding
J. Biol. Chem.
Desensitization of cell signalling mediated by phosphoinositidase C
Trends Pharmacol. Sci.
Rapid desensitization of GnRH-stimulated intracellular signalling events in αT3-1 and HEK-293 cells expressing the GnRH receptor
Endocrinology
Inositol trisphosphate and calcium signalling
Nature
Effects of extracellular nucleotides in the pituitary: ATP receptor-mediated responses in gonadotrope-derived αT3-1 cells
Endocrinology
Absence of rapid desensitization of the mouse gonadotrophin-releasing hormone receptor
Biochem. J.
Refractoriness of the pituitary gland after continuous exposure to luteinizing hormone releasing hormone
J. Endocrinol.
Model systems for the study of seven transmembrane segment receptors
Ann. Rev. Biochem.
Oxytocin receptor-mediated activation of phosphoinositidase C and elevation of cytosolic calcium in the gonadotrope-derived αT3-1 cell line
Endocrinology
Role of β-arrestin in mediating agonist-promoted G-protein-coupled receptor internalization
Science
Relative roles of calcium derived from intra- and extracellular sources in dynamic LH release from perifused pituitary cells
Mol. Endocrinol.
Cited by (79)
Gonadotropin-Releasing Hormone Receptors and Signaling
2021, Cellular Endocrinology in Health and Disease, Second EditionThe wonderful and masterful G protein-coupled receptor (GPCR): A focus on signaling mechanisms and the neuroendocrine control of fertility
2020, Molecular and Cellular EndocrinologyEvolution of the regulatory mechanisms for the hypothalamic-pituitary-gonadal axis in vertebrates–hypothesis from a comparative view
2019, General and Comparative EndocrinologyGonadotropin regulation by pulsatile GnRH: Signaling and gene expression
2018, Molecular and Cellular EndocrinologyGonadotropin-releasing hormone signaling: An information theoretic approach
2018, Molecular and Cellular EndocrinologyRegulation of reproduction via tight control of gonadotropin hormone levels
2018, Molecular and Cellular Endocrinology