The studies proposed are focused on the mechanisms involved in the regulation of short-term synthesis of dopamine (DA) and on regulation of TH in vivo in specific brain regions by typical and atypical antipsychotic drugs (APD). The phosphorylation and activation of TH by multiple protein kinases at different serine (Ser)-containing phosphorylation sites of TH will be investigated. The applicants propose to determine whether antibodies directed against segments of the enzyme-containing specific phosphorylation sites of TH alter the enzyme activity by inducing a conformational change of the enzyme and/or by neutralizing a segment of the enzyme which exerts an inhibitory effect on the catalytic activity. The distribution of different forms of TH will be investigated in non- human primate brain and in postmortem human brains from patients with psychiatric and neurological disorders and from corresponding controls. The functional consequences of removal of Ser at a specific phosphorylation site in TH and substitution with another amino acid AA, or substitution of an AA adjacent to Ser with another AA, on basal activity and on phosphorylation of the enzyme by various protein kinases will be determined. The mechanisms by which acute administration of APD elicits activation and protein kinase-mediated phosphorylation of TH, and chronic administration elicits deactivation and dephosphorylation of the enzyme will be investigated.
Showing the most recent 10 out of 22 publications
