DOWN-REGULATION AND DESENSITIZATION OF THE MUSCARINIC M(1) AND M(2) RECEPTORS IN TRANSFECTED FIBROBLAST B82 CELLS

Murine fibroblast cell lines stably transfected with the rat muscarini c m1 or m2 receptor genes were used to study the homologous regulation of the muscarinic M(1) or M(2) receptors. The cells were pretreated w ith the muscarinic receptor agonists, (+)-cismethyl-dioxolane, carbach ol, dimethyl-3-methylene-1-oxa-8-aza-spiro-[4,5]decane ((+) or (-)-YM7 96) or the muscarinic receptor antagonist atropine for up to 24 h. Our study has demonstrated that the muscarinic receptor nonselective full agonist, (+)-cismethyl-dioxolane, induced the down-regulation of both the muscarinic M(1) and the M(2) receptors in association with desens itization of the receptor-mediated functions. The muscarinic M(1) rece ptors are down-regulated without significant receptor internalization while the muscarinic M(2) receptors are more sensitive to down-regulat ion than the muscarinic M(1) receptors because of significant internal ization of the muscarinic M(2) receptors in our system. The muscarinic M(1) receptor partial agonist, (-)-YM796 induced less down-regulation and no significant desensitization of the muscarinic M(1) receptors w ith no substantial effect on the muscarinic M(2) receptor density or f unction.