Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
1999 Mar 01;1265:1097-106. doi: 10.1038/sj.bjp.0702415.
Show Gene links
Show Anatomy links
Inverse agonist abolishes desensitization of a constitutively active mutant of thyrotropin-releasing hormone receptor: role of cellular calcium and protein kinase C.
Grimberg H
,
Zaltsman I
,
Lupu-Meiri M
,
Gershengorn MC
,
Oron Y
.
???displayArticle.abstract???
1. C335Stop is a constitutively active mutant of the TRH receptor (TRH-R). To investigate the mechanism of the decreased responsiveness of C335Stop TRH-R, we studied cellular Ca2+ concentrations ([Ca2+]i) in AtT20 cells stably transfected with C335Stop TRH-R cDNA, or Ca2+-activated chloride currents in Xenopus laevis oocytes expressing this mutant receptor after injection of cRNA. The competitive TRH-R binding antagonist, chlorodiazepoxide (CDE), was used as an inverse agonist to study the contribution of constitutive activity to desensitization. 2. Acute treatment with CDE resulted in a rapid (within minutes) decrease in [Ca2+]i and an increase in the response amplitude to TRH with no measurable change in receptor density. Conversely, removal of chronically administered CDE caused a rapid increase in [Ca2+]i and a decrease in TRH response amplitude. 3. CDE abolished heterologous desensitization induced by C335Stop TRH-R on muscarinic m1-receptor (ml-R) co-expressed in Xenopus oocytes. 4. Chelation of extracellular calcium with EGTA caused a rapid decrease in [Ca2+]i and a concomitant increase in the response to TRH in AtT20 cells expressing C335Stop TRH-Rs. 5. Chelerythrine, a specific inhibitor of protein kinase C (PKC), reversed the heterologous desensitization of the response to acetylcholine (ACh). The phosphoserine/phosphothreonine phosphatase inhibitor, okadaic acid, abolished the effect of chelerythrine. 6. Down-regulation of PKC by chronic exposure to phorbol 12-myristate 13-acetate (PMA) or acute inhibition with chelerythrine caused a partial resensitization of the response to TRH. 7. Western analysis indicated that the alpha subtype of protein kinase C was down-regulated in cells expressing C335Stop TRH-Rs. Following a 5 min exposure to PMA, the residual alphaPKC translocated to the particular fraction. 8. We propose that cells expressing the constitutively active mutant TRH-R rapidly desensitize their response, utilizing a mechanism mediated by an increase in [Ca2+]i and PKC.
Ancellin,
Homologous and heterologous acute desensitization of vasopressin V1a receptor in Xenopus oocytes.
1998, Pubmed,
Xenbase
Ancellin,
Homologous and heterologous acute desensitization of vasopressin V1a receptor in Xenopus oocytes.
1998,
Pubmed
,
Xenbase
Bradford,
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
1976,
Pubmed
Cai,
delta Opioid receptor in neuronal cells undergoes acute and homologous desensitization.
1996,
Pubmed
Chuang,
G protein-coupled receptors: heterologous regulation of homologous desensitization and its implications.
1996,
Pubmed
Drummond,
Use of receptor antagonist in elucidating the mechanism of action of TRH in GH3 cells.
1989,
Pubmed
Eto,
The role of the calpain-calpastatin system in thyrotropin-releasing hormone-induced selective down-regulation of a protein kinase C isozyme, nPKC epsilon, in rat pituitary GH4C1 cells.
1995,
Pubmed
Findlay,
Three-dimensional modelling of G protein-linked receptors.
1990,
Pubmed
Gershengorn,
Evidence for tight coupling of receptor occupancy by thyrotropin-releasing hormone to phospholipase C-mediated phosphoinositide hydrolysis in rat pituitary cells: use of chlordiazepoxide as a competitive antagonist.
1986,
Pubmed
Gilkes,
Phorbol ester activation of protein kinase C inhibits CNP-stimulated cyclic GMP production in the mouse AtT-20 pituitary tumour cell line.
1994,
Pubmed
Grynkiewicz,
A new generation of Ca2+ indicators with greatly improved fluorescence properties.
1985,
Pubmed
Hasegawa,
Two isoforms of the prostaglandin E receptor EP3 subtype different in agonist-independent constitutive activity.
1996,
Pubmed
Heinflink,
A constitutively active mutant thyrotropin-releasing hormone receptor is chronically down-regulated in pituitary cells: evidence using chlordiazepoxide as a negative antagonist.
1995,
Pubmed
Jinsi-Parimoo,
Constitutive activity of native thyrotropin-releasing hormone receptors revealed using a protein kinase C-responsive reporter gene.
1997,
Pubmed
Kjelsberg,
Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation.
1992,
Pubmed
Lefkowitz,
G-protein-coupled receptors. Turned on to ill effect.
1993,
Pubmed
Lipinsky,
Contribution of response kinetics to the response pattern: studies of responses to thyrotropin-releasing hormone in Xenopus oocytes.
1995,
Pubmed
,
Xenbase
Lipinsky,
Desensitization of the response to thyrotropin-releasing hormone in Xenopus oocytes is an amplified process that precedes calcium mobilization.
1995,
Pubmed
,
Xenbase
Lupu-Meiri,
Dual regulation by protein kinase C of the muscarinic response in Xenopus oocytes.
1989,
Pubmed
,
Xenbase
Lupu-Meiri,
Extracellular calcium participates in responses to acetylcholine in Xenopus oocytes.
1990,
Pubmed
,
Xenbase
Lupu-Meiri,
Calcium entry in Xenopus oocytes: effects of inositol trisphosphate, thapsigargin and DMSO.
1993,
Pubmed
,
Xenbase
Matus-Leibovitch,
Truncation of the thyrotropin-releasing hormone receptor carboxyl tail causes constitutive activity and leads to impaired responsiveness in Xenopus oocytes and AtT20 cells.
1995,
Pubmed
,
Xenbase
McFerran,
Effects of protein kinase C activators upon the late stages of the ACTH secretory pathway of AtT-20 cells.
1994,
Pubmed
McFerran,
Involvement of multiple protein kinase C isozymes in the ACTH secretory pathway of AtT-20 cells.
1995,
Pubmed
O'Dowd,
Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor.
1989,
Pubmed
Oron,
Mechanism of membrane electrical response to thyrotropin-releasing hormone in Xenopus oocytes injected with GH3 pituitary cell messenger ribonucleic acid.
1987,
Pubmed
,
Xenbase
Parker,
Truncation of the extended carboxyl-terminal domain increases the expression and regulatory activity of the avian beta-adrenergic receptor.
1991,
Pubmed
Parma,
Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas.
1993,
Pubmed
Perlman,
Thyrotropin-releasing hormone stimulation of phosphoinositide hydrolysis desensitizes. Evidence against mediation by protein kinase C or calcium.
1991,
Pubmed
Premont,
Protein kinases that phosphorylate activated G protein-coupled receptors.
1995,
Pubmed
Prézeau,
Changes in the carboxyl-terminal domain of metabotropic glutamate receptor 1 by alternative splicing generate receptors with differing agonist-independent activity.
1996,
Pubmed
Ren,
Constitutively active mutants of the alpha 2-adrenergic receptor.
1993,
Pubmed
Richardson,
Regulation of human interleukin-8 receptor A: identification of a phosphorylation site involved in modulating receptor functions.
1995,
Pubmed
Roth,
5-Hydroxytryptamine2A (5-HT2A) receptor desensitization can occur without down-regulation.
1995,
Pubmed
Samama,
A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.
1993,
Pubmed
Samama,
Negative antagonists promote an inactive conformation of the beta 2-adrenergic receptor.
1994,
Pubmed
Shapira,
Activation of two different receptors mobilizes calcium from distinct stores in Xenopus oocytes.
1990,
Pubmed
,
Xenbase
Shenker,
A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty.
1993,
Pubmed
Straub,
Expression cloning of a cDNA encoding the mouse pituitary thyrotropin-releasing hormone receptor.
1990,
Pubmed
,
Xenbase
Tiberi,
High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype.
1994,
Pubmed
Ueda,
Protein kinase C involvement in homologous desensitization of delta-opioid receptor coupled to Gi1-phospholipase C activation in Xenopus oocytes.
1995,
Pubmed
,
Xenbase
Vale,
Synthetic TRF (thyrotropin releasing factor) analogues. II. pGlu-N3imMe-His-Pro-NH2: a synthetic analogue with specific activity greater than that of TRF2.
1971,
Pubmed
Zhang,
Protein kinase C modulation of cardiomyocyte angiotensin II and vasopressin receptor desensitization.
1996,
Pubmed