REGULATION OF MUSCARINIC RECEPTOR EXPRESSION BY CHANGES IN MESSENGER-RNA STABILITY

Regulation of muscarinic acetylcholine receptor (mAChR) subtype mRNAs was investigated in the human neuroblastoma cell line IMR-32 and in tr ansfected CHO cells. IMR-32 cells express both m1 and m3 subtypes of m AChR. Exposure of IMR-32 cells to the muscarinic agonist, carbamylchol ine (CBC) leads to a time dependent down-regulation of mAChRs which wa s maximal by 9 hours. mAChR activation resulted in a differential regu lation of mAChR subtype mRNAs, m1 mAChR mRNA was down-regulated follow ing 12 hours of agonist treatment and was associated with a decreased stability of the receptor transcript. In contrast, the m3 mAChR mRNA w as resistant to agonist treatment for up to 24 hours. Using transfecte d CHO cells, we identified sequence elements within the 3'-untranslate d region (3'-UTR) of the m1 mAChR gene which dictate agonist-induced d estabilization of the m1 mAChR mRNA. Removal of these sequences abolis hed the ability of chronic agonist exposure to destabilize m1 mAChR mR NA. These findings suggest that sequence specific differences between m1 and m3 mAChR subtypes, which both preferentially couple to hydrolys is of phosphoinositides, may be responsible for differences in the reg ulation of mAChR gene expression.