Long-term stimulation or persistent stress produces an in-crease in activity of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine biosynthesis, in the sympathetic neurons and the adrenal medulla. The precise mechanism, however, still remains to be determined how cell stimulation increases the enzyme activity or protein (enzyme induction).
In the present study, we used cultured bovine adrenal medullary cells as a model for catecholaminergic neuron and investigated as follows ; (A) cell stimulation-signal stransduction system, (B) cell stimulation-catecholamine synthesis coupling and (C) transcriptional regulation of tyrosine hydroxylase mRNA. Concerning about (A), we reported that (1) long treatment with okadaic acid reduced carbachol-evoked secretion of catecholamines by inhibiting Ca^<2+> influx in cultured adrenal medullary cells, (2) veratridine caused the Ca^<2+> -dependent increase in diacylglycerol formation and translocation of protein kinase C to memtbranes in adre
nal medullary cells and (3) staurosporine effectively inhibited Ca^<2+> /calmodulin-dependent protein kinase II. Concerning about (B), we reported that (4) Brain natriuretic peptide stimulated the production of cyclin GMP and the activity of tyrosine hydroxylase in the cells, (5) sea urchin toxin inhibited nicotinic acetylcholine receptor-mediated synthesis and secretion of catecholamines and (6) lithium treatment stimulated catecholamine synthesis and secretion via activation of protein kinase C in cultured adrenal medullary cells. Concerning about (C), we observed that (7) okadaic acid stimulated the activity of tyrosine hydroxylase but attenuated the level of its mRNA and (8) hypertonic NaCl medium enhanced both the activity and mRNA of tyrosine hydroxylase in cultured adrenal medullary cells. It is interesting to note that there is a relationship between the activity and the mRNA level of tyrosine hydroxylase but not always. We must further study the coupling for cell stimulation-transcription of tyrosine hydroxylase in adrenal medulla as well as sympathetic neurons and the brain. Less