The tail of the gonadotrophin-releasing hormone receptor: desensitization at, and distal to, G protein-coupled receptors

1999 ◽  
Vol 151 (1-2) ◽  
pp. 129-136 ◽  
Author(s):  
Craig A. McArdle ◽  
James S. Davidson ◽  
Gary B. Willars
Keyword(s):  
G Protein ◽  
Hormone Receptor ◽  
G Protein Coupled Receptors ◽  
Receptor Desensitization ◽  
Releasing Hormone ◽  
Gonadotrophin Releasing Hormone ◽  
G Protein Coupled

scholarly journals Mammalian Type I Gonadotropin-Releasing Hormone Receptors Undergo Slow, Constitutive, Agonist-Independent Internalization

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1415-1422 ◽  
Author(s):  
Adam J. Pawson ◽  
Elena Faccenda ◽  
Stuart Maudsley ◽  
Zhi-Liang Lu ◽  
Zvi Naor ◽  
...  
Keyword(s):  
G Protein ◽  
Regulatory Elements ◽  
Gnrh Receptor ◽  
G Protein Coupled Receptors ◽  
Receptor Internalization ◽  
Type I ◽  
Receptor Desensitization ◽  
Gnrh Receptors ◽  
Carboxyl Terminal ◽  
G Protein Coupled

Regulatory elements present in the cytoplasmic carboxyl-terminal tails of G protein-coupled receptors contribute to agonist-dependent receptor desensitization, internalization, and association with accessory proteins such as β-arrestin. The mammalian type I GnRH receptors are unique among the rhodopsin-like G protein-coupled receptors because they lack a cytoplasmic carboxyl-terminal tail. In addition, they do not recruit β-arrestin, nor do they undergo rapid desensitization. By measuring the internalization of labeled GnRH agonists, previous studies have reported that mammalian type I GnRH receptors undergo slow agonist-dependent internalization. In the present study, we have measured the internalization of epitope-tagged GnRH receptors, both in the absence and presence of GnRH stimulation. We demonstrate that mammalian type I GnRH receptors exhibit a low level of constitutive agonist-independent internalization. Stimulation with GnRH agonist did not significantly enhance the level of receptor internalization above the constitutive level. In contrast, the catfish GnRH and rat TRH receptors, which have cytoplasmic carboxyl-terminal tails, displayed similar levels of constitutive agonist-independent internalization but underwent robust agonist-dependent internalization, as did chimeras of the mammalian type I GnRH receptor with the cytoplasmic carboxyl-terminal tails of the catfish GnRH receptor or the rat TRH receptor. When the carboxyl-terminal Tyr325 and Leu328 residues of the mammalian type I GnRH receptor were replaced with alanines, these two mutant receptors underwent significantly impaired internalization, suggesting a function for the Tyr-X-X-Leu sequence in mediating the constitutive agonist-independent internalization of mammalian type I GnRH receptors. These findings provide further support for the underlying notion that the absence of the cytoplasmic carboxyl-terminal tail of the mammalian type I GnRH receptors has been selected for during evolution to prevent rapid receptor desensitization and internalization to allow protracted GnRH signaling in mammals.

scholarly journals Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

1997 ◽  
Vol 322 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Stephan K. BÖHM ◽  
Eileen F. GRADY ◽  
Nigel W. BUNNETT
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Extracellular Fluid ◽  
Cellular Responses ◽  
Drug Tolerance ◽  
G Protein Coupled Receptors ◽  
Regulatory Mechanisms ◽  
Receptor Desensitization ◽  
Down Regulation ◽  
G Protein Coupled

The large and functionally diverse group of G-protein-coupled receptors includes receptors for many different signalling molecules, including peptide and non-peptide hormones and neurotransmitters, chemokines, prostanoids and proteinases. Their principal function is to transmit information about the extracellular environment to the interior of the cell by interacting with the heterotrimeric G-proteins, and they thereby participate in many aspects of regulation. Cellular responses to agonists of these receptors are usually rapidly attenuated. Mechanisms of signal attenuation include removal of agonists from the extracellular fluid, receptor desensitization, endocytosis and down-regulation. Agonists are removed by dilution, uptake by transporters and enzymic degradation. Receptor desensitization is mediated by receptor phosphorylation by G-protein receptor kinases and second-messenger kinases, interaction of phosphorylated receptors with arrestins and receptor uncoupling from G-proteins. Agonist-induced receptor endocytosis also contributes to desensitization by depleting the cell surface of high-affinity receptors, and recycling of internalized receptors contributes to resensitization of cellular responses. Receptor down-regulation is a form of desensitization that occurs during continuous, long-term exposure of cells to receptor agonists. Down-regulation, which may occur during the development of drug tolerance, is characterized by depletion of the cellular receptor content, and is probably mediated by alterations in the rates of receptor degradation and synthesis. These regulatory mechanisms are important, as they govern the ability of cells to respond to agonists. A greater understanding of the mechanisms that modulate signalling may lead to the development of new therapies and may help to explain the mechanism of drug tolerance.

scholarly journals Identification and Functional Analysis of G Protein-Coupled Receptors in 20-Hydroxyecdysone Signaling From the Helicoverpa armigera Genome

2021 ◽  
Vol 9 ◽  
Author(s):  
Yan-Li Li ◽  
Yan-Xue Li ◽  
Xiao-Pei Wang ◽  
Xin-Le Kang ◽  
Ke-Qin Guo ◽  
...  
Keyword(s):  
G Protein ◽  
Helicoverpa Armigera ◽  
Hormone Receptor ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Pest Species ◽  
Metamorphic Stage ◽  
Adipokinetic Hormone ◽  
Helicoverpa Armígera ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors in animals and humans, which transmit various signals from the extracellular environment into cells. Studies have reported that several GPCRs transmit the same signal; however, the mechanism is unclear. In the present study, we identified all 122 classical GPCRs from the genome of Helicoverpa armigera, a lepidopteran pest species. Twenty-four GPCRs were identified as upregulated at the metamorphic stage by comparing the transcriptomes of the midgut at the metamorphic and feeding stages. Nine of them were confirmed to be upregulated at the metamorphic stage. RNA interference in larvae revealed the prolactin-releasing peptide receptor (PRRPR), smoothened (SMO), adipokinetic hormone receptor (AKHR), and 5-hydroxytryptamine receptor (HTR) are involved in steroid hormone 20-hydroxyecdysone (20E)-promoted pupation. Frizzled 7 (FZD7) is involved in growth, while tachykinin-like peptides receptor 86C (TKR86C) had no effect on growth and pupation. Via these GPCRs, 20E regulated the expression of different genes, respectively, including Pten (encoding phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase), FoxO (encoding forkhead box O), BrZ7 (encoding broad isoform Z7), Kr-h1 (encoding Krüppel homolog 1), Wnt (encoding Wingless/Integrated) and cMyc, with hormone receptor 3 (HHR3) as their common regulating target. PRRPR was identified as a new 20E cell membrane receptor using a binding assay. These data suggested that 20E, via different GPCRs, regulates different gene expression to integrate growth and development.

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