Differences in interactions with the dopamine transporter as revealed by diminishment of Na(+) gradient and membrane potential: dopamine versus other substrates.
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Zhen J, Chen N, Reith ME
Differences in interactions with the dopamine transporter as revealed by diminishment of Na(+) gradient and membrane potential: dopamine versus other substrates.
Neuropharmacology. 2005 Nov;49(6):769-79. Epub 2005 Aug 24.
- PubMed ID
- 16122767 [ View in PubMed]
- 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, beta-phenethylamine, p-tyramine, and MPP(+), in inhibiting binding of the cocaine analog [(3)H]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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Dextroamphetamine Sodium-dependent dopamine transporter Protein Humans YesNegative modulatorDetails