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Am J Physiol Cell Physiol 275: C636-C645, 1998;
0363-6143/98 $5.00
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Vol. 275, Issue 3, C636-C645, September 1998

Carbachol-induced desensitization of PLC-beta pathway in rat myometrium: downregulation of Gqalpha /G11alpha

Sandrine Lajat, Simone Harbon, and Zahra Tanfin

Signalisation et Régulations Cellulaires, Centre National de la Recherche Scientifique, EP1088, Université Paris-Sud, 91405 Orsay Cedex, France

In the estrogen-treated rat myometrium, carbachol increased the generation of inositol phosphates by stimulating the muscarinic receptor-Gq/G11-phospholipase C-beta 3 (PLC-beta 3) cascade. Exposure to carbachol resulted in a rapid and specific (homologous) attenuation of the subsequent muscarinic responses in terms of inositol phosphate production, PLC-beta 3 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.

inositol phosphates; muscarinic receptors; desensitized receptors; phospholipase C-beta 3 translocation; myometrial contraction


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Stepping back and looking forward: downregulation of G proteins as a mechanism of desensitization in tissues Focus on "Carbachol-induced desensitization of PLC-beta pathway in rat myometrium: downregulation of Gqalpha /G11alpha "
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