Role of calmodulin in neurotransmitter synthesis.

Tyrosine 3-monooxygenase (EC 1.14.16.2) and tryptophan 5-monooxygenase (EC 1.14.16.4) are generally believed to be the rate-limiting enzymes in the biosynthesis of the neurotransmitters, catecholamines and serotonin, respectively, and therefore the regulation of their activities is of particular importance. At least three calmodulin-dependent protein kinases differed in their molecular weights and substrate specificities, designated I, II, and III in the order of decreasing molecular weight, in rat brain cytosol. Among them, calmodulin-dependent protein kinase II with a molecular weight of about 540,000 appeared to occur only in the nervous tissues. Kinase II was found, on the one hand, to phosphorylate tyrosine 3-monooxygenase and tryptophan 5-monooxygenase, leading to the activation of these monooxygenases in the presence of activator protein and, on the other hand, to phosphorylate tubulin and microtubule-associated protein 2, which results in disassembly of the microtubules that had been assembled. These results suggest the possibility that both the secretion and biosynthesis of monoamine neurotransmitters stimulated by Ca2+ influx in the nervous system may be regulated by calmodulin-dependent protein kinase II via the phosphorylation of microtubule proteins and the phosphorylation of the monooxygenases that are the rate-limiting enzymes in the biosynthesis of the neurotransmitters.