REGULATION OF THE CATECHOLAMINE BIOSYNTHETIC ENZYMES

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This proposal seeks to study several aspects of the regulation of important neurotransmitter enzymes, their reaction constituents, and the receptors which they stimulate and which in turn initiate critical cellular events. The application is a competing renewal to support our ongoing work in these areas. The main thrust of the work is regulation of neurotransmitter enzymes and receptors from a cellular, metabolic and genetic standpoint. The work will be carried out in brain and in adrenal both in vivo and in vitro. The projects to be conducted are: (A) regulation of phenylethanolamine N-methyltransferase (PNMT) turnover by glucocorticoids, by S-adenosylmethionine and by splanchnic neuronal neurotransmitters; (B) regulation of S-adenosylmethionine (SAM) levels by glucocorticoids and other factors; (C) regulation of hydroxyindole O-methyltransferase (HIOMT) turnover by glucocorticoids; (D) regulation of dopamine beta-hydroxylase (DBH) proteolysis in vivo by ascorbic acid; (E) isolation and characterization of the proteases which degrade PNMT and DBH in vivo; (F) genetic regulation of DBH turnover; (G) genetics of PNMT responsiveness in mice; (H) genetics of serotonin, serotonin enzymes and serotonin receptors in inbred mice and (1) deveopment of monoclonal antibodies to PNMT, DBH, HIOMT and the enzymes of S-adenosylmethionine metabolism.