CARBACHOL-INDUCED DESENSITIZATION OF PLC-BETA PATHWAY IN RAT MYOMETRIUM - DOWN-REGULATION OF GQ-ALPHA G11-ALPHA/

In the estrogen-treated rat myometrium, carbachol increased the genera tion of inositol phosphates by stimulating the muscarinic receptor-G(q )/G(11)-phospholipase C-beta 3 (PLC-beta 3) cascade. Exposure to carba chol resulted in a rapid and specific (homologous) attenuation of the subsequent muscarinic responses in terms of inositol phosphate product ion, PLC-beta 3 translocation to membrane, and contraction. Refractori ness was accompanied by a reduction of membrane muscarinic binding sit es 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 muscari nic refractoriness was PKC independent and was associated with a downr egulation of G(q)alpha/G(11)alpha. Atropine failed to induce desensiti zation as well as G(q)alpha/G(11)alpha downregulation, indicating that both events involve active occupancy of the receptor. Prolonged expos ure to A1F(4)(-), reduced subsequent A1F(4)(-) as well as carbachol-me diated inositol phosphate responses and similarly induced downregulati on of G(q)alpha/G(11)alpha. Data suggest that a decrease in the level of G(q)alpha/G(11)alpha is subsequent to its activation and may accoun t for heterologous desensitization.