Nicotinic induction of preproenkephalin and tyrosine hydroxylase gene expression in butyrate-differentiated rat PC12 cells: A model for adaptation to gut-derived environmental signals

Accelerated maturation of peripheral sympathoadrenal transmitter levels and function occurs at 7-10 postnatal days in the rat. This event is temporally disconnected from the timing of major changes in physiologic stimuli evident after the birthing process (i.e. temperature, oxygen, sound, light, etc.). Colonization of the gut, fermentation of carbohydrates, and production of short-chain fatty acids (e.g. butyrate) mirrors this postnatal time course. In this report, we examined the interaction between butyrate differentiation of rat pheochromocytoma cells and cholinergic-nicotinic induction of the neuropeptide (enkephalin) and catecholamine-related biosynthetic enzymes (tyrosine hydroxylase, dopamine beta-hydroxylase, phenylethanolamine N-methyltransferase). Our results show that butyrate induces both preproenkephalin and tyrosine hydroxylase mRNA through a proximal promoter region and that this regulatory step is time and dose dependent. Moreover, there is an additional interaction with cholinergic-nicotinic inducible mechanisms consistent with classically described transsynaptic cholinergic regulation of these genes. Dopamine beta-hydroxylase and phenylethanolamine N-methyltransferase promoters were not affected by butyrate treatment. We speculate that colonization of the human gut (along with the attendant fermentation of enteral carbohydrates to short-chain fatty acids) may represent a mechanism through which environmental signals affect postnatal maturation of sympathoadrenal transmitter systems.