Cholera toxin and dibutyryl cyclic adenosine 3',5'-monophosphate sensitize gonadotropin-releasing hormone-stimulated inositol phosphate production to inhibition in protein kinase-C (PKC)-depleted cells: evidence for cross-talk between a cholera toxin-sensitive G-protein and PKC.

Desensitization of gonadotropin release by the pituitary gland in response to gonadotropin-releasing hormone (GnRH) agonists has clinical applications in the treatment of gonadal-hormone-dependent disorders. We therefore investigated possible desensitization of inositol phosphate (IP) responses of GNRH receptors. No short-term homologous desensitization of the IP response to GnRH was observed in either alpha T3 gonadotrope cells line or GH3 cells transfected with GnRH receptor cDNA. The absence of homologous desensitization is unusual among G-protein-coupled receptors, and may be due to the absence of a C-terminal cytoplasmic tail, a unique feature of the GnRH receptor. Several potential protein kinase C phosphorylation sites which might mediate heterologous desensitization are present on the GnRH receptor. In both alpha T3 cells and GnRH-receptor-transfected Cos-1 cells, activation of protein kinase C by pretreatment with phorbol ester caused a 35-53% decrease in the IP response to GnRH. However, phorbol ester also inhibited guanosine 5′-[gamma-thio]triphosphate-stimulated IP production in permeabilized Cos-1 cells, suggesting that this inhibition is mediated at a post-receptor site.

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Signal transduction of the gonadotropin releasing hormone (GnRH) receptor: Cross-talk of calcium, protein kinase C (PKC), and arachidonic acid

Cellular and Molecular Neurobiology ◽

10.1007/bf02071315 ◽

1995 ◽

Vol 15 (5) ◽

pp. 527-544 ◽

Cited By ~ 29

Author(s):

Zvi Naor ◽

Sharon Shacham ◽

Dagan Harris ◽

Rony Seger ◽

Nachum Reiss

Keyword(s):

Signal Transduction ◽

Arachidonic Acid ◽

Protein Kinase C ◽

Protein Kinase ◽

Cross Talk ◽

Gnrh Receptor ◽

Gonadotropin Releasing Hormone ◽

Releasing Hormone ◽

Kinase C ◽

Receptor Cross Talk

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Scrape-loaded p21ras down-regulates agonist-stimulated inositol phosphate production by a mechanism involving protein kinase C

Biochemical Journal ◽

10.1042/bj2600157 ◽

1989 ◽

Vol 260 (1) ◽

pp. 157-161 ◽

Cited By ~ 13

Author(s):

B D Price ◽

J D H Morris ◽

C J Marshall ◽

A Hall

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Inositol Phosphate ◽

Platelet Derived Growth Factor ◽

3T3 Cells ◽

Ras Protein ◽

Kinase C ◽

Inositol Phosphate Production ◽

Ligand Stimulation ◽

Scrape Loading

The effect of scrape-loaded [Val-12]p21ras on agonist-stimulated phosphatidylinositol 4,5-bisphosphate (PIP2) turnover in Swiss-3T3 cells was studied. Previously [Morris, Price, Lloyd, Marshall & Hall (1989) Oncogene 4, 27-31] we demonstrated that [Val-12]p21ras activates protein kinase C within 10 min of scrape loading. Here, we show that [Val-12]p21ras inhibits bombesin and platelet-derived growth factor-stimulated PIP2 breakdown 1.5-4 h after scrape loading. This effect persisted for at least 18 h and could be mimicked in control cells by activation of protein kinase C with 12-O-tetradecanoyl 13-acetate (TPA) 15 min prior to ligand stimulation. When protein kinase C was down-regulated by chronic TPA treatment, [Val-12]p21ras was no longer able to inhibit agonist-stimulated inositol phosphate production. These results indicate that changes in inositol phosphate levels caused by ras protein are probably due to activation of protein kinase C and not to an interaction of ras with phospholipase C.

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