AGONIST-INDUCED DESENSITIZATION OF THE MU-OPIOID RECEPTOR-COUPLED POTASSIUM CHANNEL (GIRK1)

In Xenopus oocytes expressing the rat mu receptor and the G protein-ga ted, inwardly rectifying K+ channel (known as KGA or GIRK1), applicati on of [D-Ala(2),MePhe(4),Glyol(5)]enkephalin) , a mu opioid agonist, e voked a dose-dependent increase in KC conductance, With sustained agon ist exposure, the amplitude of the response decayed with a t(1/2) of 8 +/- 2 min. In oocytes coexpressing the mu and 5HT1A receptors with GI RK1, stimulation of either receptor resulted in heterologous desensiti zation of the subsequent response to the other, Injection of guanosine 5'-O-(thiotriphosphate) (1 mM) increased the basal GIRK1 activity and the total response to the application of agonist, but did not affect the rate of desensitization. Basal channel activity in the absence of agonist also desensitized at the same rate when the oocytes were expos ed to high K+ (96 mM) solution, The above results indicate that the de sensitization of the response occurred at a site downstream of the rec eptor, possibly at the channel, The rate of desensitization was not si gnificantly altered by any of the following treatments: removal of ext ernal Ca2+, preloading the oocytes with ,2-bis(o-aminophenoxy)ethane-N ,N,N',N'-tetraacetic acid-tetra-(acetoxymethyl)-ester (0.5-1 mM), elev ation of cAMP levels, treatment with phorbol esters (1 mu M), staurosp orine (0.5 mu M), okadaic acid (1 mu M), Or cytochalasin B (0.5 mu M). These results suggest that desensitization may not involve a calcium or phosphorylation-dependent mechanism.