THE CHROMAFFIN GRANULE AND SYNAPTIC VESICLE AMINE TRANSPORTERS DIFFERIN SUBSTRATE RECOGNITION AND SENSITIVITY TO INHIBITORS

Classical studies using bovine chromaffin granules have defined the ph ysiologic and pharmacologic properties of the vesicular amine transpor ter that packages monoamine transmitters into intracellular vesicles f or subsequent regulated release. The recent isolation of two distinct but closely related cDNA clones encoding vesicular amine transport sug gests that the activity expressed in the brain (synaptic vesicle amine transporter or SVAT) may differ significantly from the previously des cribed adrenal gland activity (chromaffin granule amine transporter or CGAT). A direct comparison of the two transporters now shows that SVA T has a higher affinity than CGAT for monoamine substrates, in particu lar for histamine. In addition, SVAT shows approximately 10-fold great er sensitivity to tetrabenazine than CGAT. [H-3]Dihydrotetrabenazine s hows no detectable binding to CGAT but does bind to SVAT, accounting f or the differential sensitivity. Furthermore, methamphetamine preferen tially inhibits transport by SVAT relative to CGAT, apparently by comp eting at the site of amine recognition rather than by disrupting the v esicular pH gradient. These previously unsuspected differences in the storage of monoamine transmitter in the central nervous system and the adrenal gland may help to account for several classic pharmacological observations.