Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8998276 | Neuropharmacology | 2005 | 11 Pages |
Abstract
In heterologous cells expressing the dopamine transporter (DAT), simultaneous elevation of intracellular Na+ and depolarization of the membrane with gramicidin reduced the potency of various DAT substrates, including dopamine, d-amphetamine, β-phenethylamine, p-tyramine, and MPP+, in inhibiting binding of the cocaine analog [3H]CFT, with the greatest reduction observed for d-amphetamine. In rat striatal synaptosomes, gramicidin exerted similar effects; in addition, the potency of d-amphetamine was reduced by the Na+-channel activator veratridine. The latter effect was counteracted by the Na+-channel blocker tetrodotoxin. In broken membranes, where, as the situation with gramicidin, both sides of the non-polarized membrane were exposed to 130 mM Na+, gramicidin was ineffective. Dopamine had a potency for membrane preparations that was not significantly different from that for control cells or synaptosomes, while other substrates had potencies for membrane preparations that were reduced to a level similar to those observed in gramicidin-treated cells or synaptosomes. These results suggest that diminishing Na+ gradient and membrane potential may convert DAT to a conformational state that dopamine could easily bind to when gaining free access to its intracellular portion. In contrast, non-dopamine substrates may not be able to readily interact with this state from either side of the membrane.
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Authors
Juan Zhen, Nianhang Chen, Maarten E.A. Reith,