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Absence of rapid desensitization of the mouse gonadotropin-releasing hormone receptor
J S Davidson1, I K Wakefield, R P Millar
1Department of Chemical Pathology, University of Cape Town Medical School, Observatory, South Africa.
Abstract:
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.
Insights
Gonadotropin-releasing hormone (GnRH) receptor desensitization was studied. The GnRH receptor IP response showed no homologous desensitization but did exhibit heterologous desensitization via protein kinase C activation.
Area of Science:
- Endocrinology
- Molecular Pharmacology
- Cell Signaling
Background:
- Gonadotropin-releasing hormone (GnRH) receptor desensitization is crucial for treating hormone-dependent disorders.
- Understanding GnRH receptor signaling is key to developing targeted therapies.
Purpose of the Study:
- To investigate the desensitization of inositol phosphate (IP) responses mediated by GnRH receptors.
- To explore the mechanisms underlying GnRH receptor desensitization, focusing on homologous and heterologous pathways.
Main Methods:
- Utilized alpha T3 gonadotrope cells and GH3 cells transfected with GnRH receptor cDNA.
- Assessed IP production in response to GnRH and guanosine 5'-[gamma-thio]triphosphate.
- Investigated heterologous desensitization using phorbol ester to activate protein kinase C.
Main Results:
- No short-term homologous desensitization of the IP response to GnRH was observed in tested cell lines.
- Activation of protein kinase C by phorbol ester led to a significant decrease (35-53%) in GnRH-stimulated IP production.
- Phorbol ester also inhibited guanosine 5'-[gamma-thio]triphosphate-stimulated IP production, indicating post-receptor inhibition.
Conclusions:
- The unique structure of the GnRH receptor, lacking a C-terminal cytoplasmic tail, may explain the absence of homologous desensitization.
- Heterologous desensitization of the GnRH receptor occurs via protein kinase C activation, likely through post-receptor mechanisms.