The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors

Abstract

Classical studies using bovine chromaffin granules have defined the physiologic and pharmacologic properties of the vesicular amine transporter that packages monoamine transmitters into intracellular vesicles for subsequent regulated release. The recent isolation of two distinct but closely related cDNA clones encoding vesicular amine transport suggests that the activity expressed in the brain (synaptic vesicle amine transporter or SVAT) may differ significantly from the previously described adrenal gland activity (chromaffin granule amine transporter or CGAT). A direct comparison of the two transporters now shows that SVAT has a higher affinity than CGAT for monoamine substrates, in particular for histamine. In addition, SVAT shows approximately 10-fold greater sensitivity to tetrabenazine than CGAT. [3H]Dihydrotetrabenazine shows no detectable binding to CGAT but does bind to SVAT, accounting for the differential sensitivity. Furthermore, methamphetamine preferentially inhibits transport by SVAT relative to CGAT, apparently by competing at the site of amine recognition rather than by disrupting the vesicular 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.