THE PHARMACOLOGICAL PROFILE OF THE VESICULAR MONOAMINE TRANSPORTER RESEMBLES THAT OF MULTIDRUG TRANSPORTERS

Vesicular neurotransmitter transporters function in synaptic vesicles and other subcellular organelles and they were thought to be involved only in neurotransmitter storage, Several findings have led us to test novel aspects of their function, Cells expressing a c-DNA coding for one of the rat monoamine transporters (VMAT1) become resistant to the neurotoxin N-methyl-4-phenylpyridinium (MPP(+)) [Liu et al. (1992) Cel l, 70, 539-551]. The basis of the resistance is the VMAT1-mediated tra nsport and sequestration of the toxin into subcellular compartments. I n addition, the deduced sequence of VMAT1 predicts a protein that show s a distinct homology to a class of bacterial drug resistance transpor ters (TEXANs) that share some substrates with mammalian multidrug resi stance transporters (MDR) such as the P-glycoprotein. These findings i nduced us to test whether compounds that are typically transported by MDR interact also with vesicular transporters, The use of [H-3]reserpi ne binding to determine drug interactions with VMAT allowed assessment of the ability of various drugs to bind to the substrate site of the transporter, Cytotoxic compounds such as ethidium, isometamidium, tetr aphenylphosphonium, rhodamine, tacrine and doxorubicin, interact speci fically with vesicular monoamine transporters, Verapamil, a calcium ch annel blocker, is also a competitive inhibitor of transport, Tn the ca se of rhodamine, fluorescence measurements in digitonin-permeabilized cells demonstrated ATP-dependent VMAT-mediated transport, The results imply that even though the bacterial and vesicular transporters are st ructurally different from the P-glycoprotein, they share a similar sub strate range, These findings suggest a novel possible way of protectio n from the effects of toxic compounds by removal to subcellular compar tments.