Desensitization of Gonadotropin-releasing Hormone Action in αT3-1 Cells Due to Uncoupling of Inositol 1,4,5-Trisphosphate Generation and Ca 2+ Mobilization

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dc.contributor.authorMcArdle, Craig A
dc.contributor.authorWillars, Gary B
dc.contributor.authorFowkes, Robert C
dc.contributor.authorNahorski, Stefan R
dc.contributor.authorDavidson, James S
dc.contributor.authorForrest-Owen, Wyn
dc.date.accessioned2021-10-08T07:20:44Z
dc.date.available2021-10-08T07:20:44Z
dc.date.issued1996
dc.description.abstractGonadotropin-releasing hormone (GnRH) acts via a G-protein coupled receptor on gonadotropes to increase cytosolic Ca2+ and stimulate gonadotropin secretion. Sustained exposure causes desensitization of these effects, but the GnRH receptor has no C-terminal tail and does not undergo rapid (<5 min) desensitization. Nevertheless, pretreatment of alphaT3-1 cells with GnRH reduced the spike Ca2+ response to GnRH and decreased the GnRH effect on inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) by 30-50%. Ca2+-free medium with or without thapsigargin also decreased GnRH-stimulated Ins(1,4,5)P3 generation, implying that attenuation of the Ca2+ response underlies the Ins(1,4,5)P3 reduction rather than vice versa. Intracellular Ca2+ pool depletion cannot explain desensitization of the Ca2+ response because pool depletion and repletion were faster (half-times, <1 min) than the onset of and recovery from desensitization (half-times 10-20 min and 4-6 h). Moreover, 1-h GnRH pre-treatment attenuated the spike Ca2+ response to GnRH but not that to ionomycin, and brief GnRH exposure in Ca2+-free medium reduced the response to ionomycin more effectively in controls than in desensitized cells. GnRH pretreatment also attenuated the Ca2+ response to PACAP38. This novel form of desensitization does not reflect uncoupling of GnRH receptors from their immediate effector system but rather a reduced efficiency of mobilization by Ins(1,4,5)P3 of Ca2+ from an intact intracellular pool.
dc.identifier.apacitationMcArdle, C. A., Willars, G. B., Fowkes, R. C., Nahorski, S. R., Davidson, J. S., & Forrest-Owen, W. (1996). Desensitization of Gonadotropin-releasing Hormone Action in αT3-1 Cells Due to Uncoupling of Inositol 1,4,5-Trisphosphate Generation and Ca 2+ Mobilization. <i>The Journal of Biological Chemistry</i>, 271(39), 23711 - 23717. http://hdl.handle.net/11427/34995en_ZA
dc.identifier.chicagocitationMcArdle, Craig A, Gary B Willars, Robert C Fowkes, Stefan R Nahorski, James S Davidson, and Wyn Forrest-Owen "Desensitization of Gonadotropin-releasing Hormone Action in αT3-1 Cells Due to Uncoupling of Inositol 1,4,5-Trisphosphate Generation and Ca 2+ Mobilization." <i>The Journal of Biological Chemistry</i> 271, 39. (1996): 23711 - 23717. http://hdl.handle.net/11427/34995en_ZA
dc.identifier.citationMcArdle, C.A., Willars, G.B., Fowkes, R.C., Nahorski, S.R., Davidson, J.S. & Forrest-Owen, W. 1996. Desensitization of Gonadotropin-releasing Hormone Action in αT3-1 Cells Due to Uncoupling of Inositol 1,4,5-Trisphosphate Generation and Ca 2+ Mobilization. <i>The Journal of Biological Chemistry.</i> 271(39):23711 - 23717. http://hdl.handle.net/11427/34995en_ZA
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.ris TY - Journal Article AU - McArdle, Craig A AU - Willars, Gary B AU - Fowkes, Robert C AU - Nahorski, Stefan R AU - Davidson, James S AU - Forrest-Owen, Wyn AB - Gonadotropin-releasing hormone (GnRH) acts via a G-protein coupled receptor on gonadotropes to increase cytosolic Ca2+ and stimulate gonadotropin secretion. Sustained exposure causes desensitization of these effects, but the GnRH receptor has no C-terminal tail and does not undergo rapid (<5 min) desensitization. Nevertheless, pretreatment of alphaT3-1 cells with GnRH reduced the spike Ca2+ response to GnRH and decreased the GnRH effect on inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) by 30-50%. Ca2+-free medium with or without thapsigargin also decreased GnRH-stimulated Ins(1,4,5)P3 generation, implying that attenuation of the Ca2+ response underlies the Ins(1,4,5)P3 reduction rather than vice versa. Intracellular Ca2+ pool depletion cannot explain desensitization of the Ca2+ response because pool depletion and repletion were faster (half-times, <1 min) than the onset of and recovery from desensitization (half-times 10-20 min and 4-6 h). Moreover, 1-h GnRH pre-treatment attenuated the spike Ca2+ response to GnRH but not that to ionomycin, and brief GnRH exposure in Ca2+-free medium reduced the response to ionomycin more effectively in controls than in desensitized cells. GnRH pretreatment also attenuated the Ca2+ response to PACAP38. This novel form of desensitization does not reflect uncoupling of GnRH receptors from their immediate effector system but rather a reduced efficiency of mobilization by Ins(1,4,5)P3 of Ca2+ from an intact intracellular pool. DA - 1996 DB - OpenUCT DP - University of Cape Town IS - 39 J1 - The Journal of Biological Chemistry LK - https://open.uct.ac.za PY - 1996 SM - 0021-9258 SM - 1083-351X T1 - Desensitization of Gonadotropin-releasing Hormone Action in αT3-1 Cells Due to Uncoupling of Inositol 1,4,5-Trisphosphate Generation and Ca 2+ Mobilization TI - Desensitization of Gonadotropin-releasing Hormone Action in αT3-1 Cells Due to Uncoupling of Inositol 1,4,5-Trisphosphate Generation and Ca 2+ Mobilization UR - http://hdl.handle.net/11427/34995 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/34995
dc.identifier.vancouvercitationMcArdle CA, Willars GB, Fowkes RC, Nahorski SR, Davidson JS, Forrest-Owen W. Desensitization of Gonadotropin-releasing Hormone Action in αT3-1 Cells Due to Uncoupling of Inositol 1,4,5-Trisphosphate Generation and Ca 2+ Mobilization. The Journal of Biological Chemistry. 1996;271(39):23711 - 23717. http://hdl.handle.net/11427/34995.en_ZA
dc.language.isoeng
dc.publisher.departmentDivision of Chemical Pathology
dc.publisher.facultyFaculty of Health Sciences
dc.sourceThe Journal of Biological Chemistry
dc.source.journalissue39
dc.source.journalvolume271
dc.source.pagination23711 - 23717
dc.source.urihttps://dx.doi.org/10.1074/jbc.271.39.23711
dc.subject.otherCalcium
dc.subject.otherCell Line
dc.subject.otherCytoplasm
dc.subject.otherDown-Regulation
dc.subject.otherGonadotropin-Releasing Hormone
dc.subject.otherInositol 1,4,5-Trisphosphate
dc.subject.otherIonomycin
dc.subject.otherNeuropeptides
dc.subject.otherPituitary Adenylate Cyclase-Activating Polypeptide
dc.subject.otherPituitary Gland, Anterior
dc.subject.otherReceptors, LHRH
dc.subject.otherSignal Transduction
dc.subject.otherType C Phospholipases
dc.subject.otherNeuropeptides
dc.titleDesensitization of Gonadotropin-releasing Hormone Action in αT3-1 Cells Due to Uncoupling of Inositol 1,4,5-Trisphosphate Generation and Ca 2+ Mobilization
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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