REGULATION OF CATECHOLAMINE SYNTHESIS - MULTIPLE MECHANISMS AND THEIR SIGNIFICANCE

Phosphorylation of tyrosine hydroxylase, the rate-limiting enzyme, by a variety of protein kinases provides multiple mechanisms for the regulation of catecholamine synthesis. This contrasts with the synthesis of acetylcholine which is the product of a single reversible reaction, controlled by the law of mass action, whose rate is determined by the concentration of acetylcholine in the compartment of acetylcholine synthesis. This results in close coupling of synthesis rate and release rate. Tyrosine hydroxylase is subject to end-product inhibition but there is no evidence that impulse-induced release of catecholamines stimulates catecholamine synthesis by removal of end-product inhibition. Tyrosine hydroxylase in its native form appears to be partially inhibited since partial trypsinisation produces activation of the enzyme which resembles that resulting from a variety of manipulations which are likely to induce a charge-dependent conformational change. Of these, phosphorylation is most likely to play a physiological role. The sites on the enzyme phosphorylated by the various protein kinases and the resulting changes in kinetic parameters are briefly reviewed. Of the four protein kinases only activation of Ca2+/CM-dependent protein kinase is directly linked to catecholamine release through the influx of Ca2+ on arrival of the action potential at the nerve terminal. The activation of cAMP-dependent protein kinase, protein kinase C and cGMP-dependent protein kinase is controlled by presynaptic receptors. The regulation of striatal dopaminergic and hippocampal noradrenergic synthesis are discussed in terms of these mechanisms for the activation of tyrosine hydroxylase. Some of the paradoxical effects seen in K+-depolarised striatal slices as well as the accelerated synthesis resulting from both increased and arrested impulse traffic are analysed in terms of receptor interactions. Regulation of synthesis in both striatal dopaminergic and hippocampal noradrenergic neurones occurs both by mechanisms which are impulse dependent and therefore closely coupled to release (Ca2+/CM-dependent and autoreceptor-mediated) and by mechanisms which are independent of the impulse traffic in these neurones and are mediated by presynaptic heteroreceptors. Whereas the former may serve to maintain a constant size of releasable transmitter pool, the latter may subserve synaptic modulation. © 1990.