Treatment of CHO cells stably expressing the human M1 muscarinic acetylcholine (HM1) receptor with the cholinergic agonist carbachol results in a reduction in cellular levels of Gq alpha/G11 alpha. Half-maximal effects are produced by 3 h, and a new steady state of some 50% of the resting levels of Gq alpha/G11 alpha is subsequently established [Mullaney, Dodd, Buckley and Milligan, (1993) Biochem. J. 289, 125-131]. To analyse the mechanism of this effect, we examined the rate of turnover of Gq alpha/G11 alpha in these HM1-expressing cells in the presence and absence of carbachol (1 mM). In untreated cells the measured removal of 35S-labelled Gq alpha/G11 alpha was adequately described by a monoexponential curve with a half-time (t0.5) of 18.0 +/- 2.2 h. When the cells were treated with carbachol a more complex pattern of Gq alpha/G11 alpha degradation was observed. Upon addition of the agonist, the rate of degradation initially increased markedly (t0.5 = 2.9 +/- 0.2 h). The maintained presence of the agonist was unable, however, to sustain the enhanced rate of degradation. Beyond 8 h of treatment with carbachol, degradation of Gq alpha/G11 alpha returned to a rate close to that observed in untreated cells (t0.5 = 18.5 +/- 1.3 h). Parallel experiments indicated that the effect of carbachol was specific for Gq alpha/G11 alpha, as the t0.5 of Gi2 alpha (approx. 30 h) was not affected by the agonist. Analysis of Gq alpha/G11 alpha mRNA levels by reverse transcriptase/PCR indicated that there was no difference in cells maintained in the absence and presence of carbachol. Such data demonstrate that agonist-induced establishment of a new steady-state level of Gq alpha/G11 alpha results from an initial receptor-mediated enhancement of protein turnover followed by a desensitization of the receptor response.