Lajat S, Harbon S, Tanfin Z
Signalisation et Régulations Cellulaires, Centre National de la Recherche Scientifique, EP1088, Université Paris-Sud, 91405 Orsay Cedex, France.
Am J Physiol. 1998 Sep;275(3):C636-45. doi: 10.1152/ajpcell.1998.275.3.C636.
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.
在雌激素处理的大鼠子宫肌层中，卡巴胆碱通过刺激毒蕈碱受体 - Gq/G11 - 磷脂酶C - β3（PLC - β3）级联反应增加肌醇磷酸的生成。暴露于卡巴胆碱会导致随后毒蕈碱反应在肌醇磷酸生成、PLC - β3向膜的转位以及收缩方面迅速且特异性（同源性）地减弱。不应性伴随着膜毒蕈碱结合位点的减少以及残余受体的解偶联状态。蛋白激酶C（PKC）改变毒蕈碱受体的功能，并促成脱敏的初始阶段。毒蕈碱不应性的延迟阶段与PKC无关，且与Gqα/G11α的下调有关。阿托品未能诱导脱敏以及Gqα/G11α下调，表明这两个事件都涉及受体的活性占据。长时间暴露于AlF - 4会降低随后AlF - 4以及卡巴胆碱介导的肌醇磷酸反应，并同样诱导Gqα/G11α的下调。数据表明，Gqα/G11α水平的降低是在其激活之后发生的，并且可能是异源脱敏的原因。
