REGULATION OF DIHYDROPYRIDINE AND RYANODINE RECEPTOR GENE-EXPRESSION IN SKELETAL-MUSCLE - ROLE OF NERVE, PROTEIN-KINASE-C, AND CAMP PATHWAYS

The dihydropyridine (DHP) and ryanodine (RY) receptors play a critical role in depolarization-induced calcium release in skeletal muscle, ye t the factors which govern their expression remain unknown. We investi gated the roles of electrical activity and trophic factors in the regu lation of the genes encoding the alpha(1), alpha(2), and beta subunits of the DHP receptor as well as the RY receptor in rat skeletal muscle in vivo. Muscle paralysis, induced by denervation, had no effect on t he DHP receptor mRNA levels while the RY receptor mRNA was decreased. In contrast, chronic superfusion of tetrodotoxin onto the sciatic nerv e resulted in a marked increase in mRNA levels and transcriptional act ivity of both DHP and RY receptor genes. Since nerve can induce change s in second messenger pathways which modulate muscle gene expression, we attempted to identify factors which regulate DHP and RY receptor ex pression using cultured myotubes. Elevated cAMP levels specifically in hibited the expression of RY receptor mRNA while 12-O-tetradecanoylpho rbol-13-acetate, an activator of protein kinase C, increased the trans cripts encoding the RY receptor and the alpha(1) subunit of the DHP re ceptor. Changes in the level of mRNAs were paralleled by altered recep tor numbers. Neither cAMP nor protein kinase C altered transcriptional activity of the DHP and RY receptor genes. These results demonstrate that neural factor(s) regulate DHP and RY receptor mRNA levels in vivo via transcriptional mechanisms while protein kinase C and cAMP can mo dulate DHP and RY receptor transcript levels by a transcription-indepe ndent process.