Dopaminergic neurons—Alteration in the kinetic properties of tyrosine hydroxylase after cessation of impulse flow

Abstract

Studies in vitro conducted on striatal tyrosine hydroxylase have demonstrated that addition of calcium chelators, such as EGTA, results in an alteration in the kinetic properties of tyrosine hydroxylase which can be completely reversed by addition of calcium to the incubation medium. Inhibition of impulse flow in the nigro-neostriatal pathway by either pharmacological or mechanical techniques causes the isolated striatal tyrosine hydroxylase to behave kinetically like the enzyme treated in vitro with EGTA. Tyrosine hydroxylase, isolated from the striatum of rats in which impulse flow has been interrupted in the dopamine pathways, has an increased affinity for both substrate and pterin cofactor and a reduced affinity for the end-product inhibitor, dopamine. The latter change is most dramatic; the K i of the enzyme for dopamine. increases more than 700-fold. These alterations in the kinetic properties of tyrosine hydroxylase can also be completely reversed by addition of calcium to the incubation medium. In rats with a pharmacological blockade of impulse flow induced by administration of γ-hydroxybutyrate, subsequent administration of dopamine receptor stimulants causes the isolated tyrosine hydroxylase to have properties similar to those observed for the enzyme prepared from untreated rats. Administration of dopamine receptor blockers prevents the dopamine receptor stimulants from altering the kinetic changes in tyrosine hydroxylase induced by a cessation of impulse flow. These data are discussed in terms of the possible role presynaptic receptors and calcium fluxes may play in the short-term regulation of tyrosine hydroxylase.