Carbachol-induced desensitization of PLC-beta pathway in rat myometrium: downregulation of Gqalpha/G11alpha.
In the estrogen-treated rat myometrium, carbachol increased the generation of inositol phosphates by stimulating the muscarinic receptor-Gq/G11-phospholipase C-beta3 (PLC-beta3) cascade. Exposure to carbachol resulted in a rapid and specific (homologous) attenuation of the subsequent muscarinic responses in terms of inositol phosphate production, PLC-beta3 translocation to membrane, and contraction. Refractoriness was accompanied by a reduction of membrane muscarinic binding sites and an uncoupled state of residual receptors. Protein kinase C (PKC) altered the functionality of muscarinic receptors and contributed to the initial period of desensitization. A delayed phase of the muscarinic refractoriness was PKC independent and was associated with a downregulation of Gqalpha/G11alpha. Atropine failed to induce desensitization as well as Gqalpha/G11alpha downregulation, indicating that both events involve active occupancy of the receptor. Prolonged exposure to AlF-4 reduced subsequent AlF-4 as well as carbachol-mediated inositol phosphate responses and similarly induced downregulation of Gqalpha/G11alpha. Data suggest that a decrease in the level of Gqalpha/G11alpha is subsequent to its activation and may account for heterologous desensitization.
Lajat
S
S
Signalisation et Régulations Cellulaires, Centre National de la Recherche Scientifique, EP1088, Université Paris-Sud, 91405 Orsay Cedex, France.
Harbon
S
S
Tanfin
Z
Z
D017607:Aluminum Compounds / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005459:Fluorides / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009215:Myometrium / Q000187:drug effects / Q000502:physiology*; D019832:N-Methylscopolamine / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D054799:Phospholipase C beta; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism*
D017607:Aluminum Compounds; D004791:Enzyme Inhibitors; D007211:Indoles; D007295:Inositol Phosphates; D007527:Isoenzymes; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; C050992:tetrafluoroaluminate; D015240:Phorbol 12,13-Dibutyrate; D007294:Inositol; D001285:Atropine; D002217:Carbachol; D010738:Type C Phospholipases; D054799:Phospholipase C beta; C518041:Plcb3 protein, rat; D019204:GTP-Binding Proteins; D005459:Fluorides; D019832:N-Methylscopolamine; C064758:Ro 31-8220