Noradrenergic neurons: allosteric activation of hippocampal tyrosine hydroxylase by stimulation of the locus coeruleus.

Robert H. Roth, Phyllis M. Salzman and Victor H. Morgenroth, III Departments of Pharmacology and Psychiatry Yale University School of Medicine New Haven, Connecticut 06510 Communicated by: Parkhurst A. Shore (Received B July 1974; accepted 23 July 1974) In peripheral noradrenergic neurons an increase in impulse flow results in an acceleration of norepinephrine biosynthesis. This increase in transmitter synthesis is due to an increase in the activity of the rate limiting enzyme tyrosine hydroxylase. Until recently this increase in tyrosine hydroxylase activity was thought to arise as a result of the removal of endproduct inhibition subsequent to the depletion of a small pool of norepinephrine which has access to tyrosine hydroxylase (1). Recent experiments in our laboratory, however, have suggested that the post-stimulation increase in tyrosine hydroxylase activity observed in sympathetic nerve endings after electrical stimulation of noradrenergic nerves occurs as a result of an allosteric activation of tyrosine hydroxylase (2). This allosteric activation appears to be mediated by an increase in affinity of the enzyme for both substrate and pteridine cofactor and a decreased affinity of the enzyme for the endproduct inhibitor norepinephrine, It is generally assumed that noradrenergic neurons in the central nervous system behave in a fashion quite similar to the postganglionic sympathetic noradrenergic neurons in the periphery. In fact, it has recently been demonstrated that stimulation of central noradrenergic neurons results in an increase in the turnover of norepinephrine as well as an increase in the accumu-