We have studied factors involved in the regulation of phospholipase C-coupled receptors in cerebellar granule cells. In response to stimulation with the muscarinic receptor agonist carbachol, both m3-and-m2-muscarinic receptor mRNA are down-regulated but with a distinct time-course. Exposure of cells to subtype-selective and nonselective antagonists induce differential up-regulation of m2- and m3-receptor mRNA. The agonist and antagonist-induced effects are associated with a respective down- and up-regulation of the muscarinic receptor transcrip- tion rate. m3-receptor mRNA and c-fos mRNA are also up-regulated by endothelin, a novel neuropeptide. Disruption of microtubules by colchicine results in a loss of muscarinic receptor number, m3-receptor mRNA, and carbachol-induced phosphoinositide turnover, while m2-receptor mRNA is markedly up-regulated. The effects of 5-HT2 receptor agonists (5-HT, DOI) and antagonists (mianserin, ketanserin) on 5-HT2 receptor mRNA expression have also been in cerebellar granule cells. Pretreatment with 5-HT or DOI induced a rapid desensitization of 5-HT2 receptor-mediated PI response and a subsequent increase of 3H-ketanserin binding to 5-HT2 receptors. The increase in 5-HT2 receptor binding was associated with an increase in both the Bmax and Kd value of 3H-ketanserin binding. Moreover, the up-regulation was temporally correlated with an increase of 5-HT2 receptor mRNA level (from 1-24 hours after treatment). Conversely, preexposure to the 5-HT2 antagonists mianserin and ketanserin induced a time-dependent decrease of 5-HT-induced response but a concurrent loss of 5-HT2 receptor binding sites. Mianserin-induced 5-HT2 receptor down-regulation was accompanied by a marked loss of 5-HT2 receptor mRNA. Thus, in cerebellar granule cells, the number of 5-HT2 receptors and 5-HT2 receptor mRNA levels are regulated by 5-HT2 receptor agonists and antagonists in an unusual manner.