THE TYRAMINE BINDING-SITE IN THE CENTRAL-NERVOUS-SYSTEM - AN OVERVIEW

The [H-3]Tyramine (TY) binding site is proposed as a high affinity mar ker of the membrane carrier for dopamine (DA) in synaptic vesicles fro m DA-rich brain regions. Under precise assay conditions, there is neit her a consistent association of TY with the neuronal, cocaine-sensitiv e DA transporter, nor with mitochondrial or microsomal targets. TY-lab eled sites have a high affinity for selected toxins such as the Parkin sonian agent MPP+ (1-methyl-4-phenylpyridinium ion), or drugs such as diphenylalkylamine Ca2+-channel antagonists. The MPP+/TY site interact ion, which in the striatum leads to depletion of vesicular DA, occurs in dopaminergic as well as in noradrenergic regions, though with diffe rent kinetic profiles. TY-labeled carriers for DA and noradrenaline (N A) in respective vesicles seem to be different entities, which might r esult in a region-specific rate of toxin sequestration and/or release from heterogeneous vesicles. Whereas MPP+ is a potent competitive-type inhibitor of [H-3]TY binding, prenylamine-like Ca2+-Channel antagonis ts can compete with TY for the vesicle site, in a tetrabenazine- or re serpine-like manner, and also inhibit TY binding thanks to the extra-c hannel directed impairment of membrane bioenergetics they are proposed to provoke. This follows from the generally-accepted assumption that similar mechanisms are operational for secretory organelles in adrenal s and CNS, and from the marked sensitivity of TY binding to miscellane ous energy-disrupting agents. A model is therefore proposed, depicting the TY-, DA- or MPP+-labeled, vesicle carrier, as a dimeric protein w hich may switch from the cytoplasm-oriented, ''recognition'' state, to the vesicle-oriented, ''transport'' state, thanks to the establishmen t of an H+-ATPase-supported, membrane protein electrochemical gradient .