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[3H]Dihydrotetrabenazine binding to bovine striatal synaptic vesicles

JA Near

[2-3H]Dihydrotetrabenazine (2-hydroxy-3-isobutyl-9, 10-dimethoxy- 1,2,3,4,6,7-hexahydro-11bH-benzo[a]quinolizine) bound to a single class of binding sites in synaptic vesicles isolated from bovine corpus striatum, with an apparent dissociation constant (Kd) of 2.3 nM and a Bmax of 15.1 pmol/mg of protein determined at equilibrium. Kinetic determination of the equilibrium dissociation constant yielded a value of 5.4 nM. ATP had no effect on the apparent Kd or Bmax, nor did it alter the kinetics of association or dissociation. Dopamine, serotonin, and other substrates for transport into synaptic vesicles inhibited binding at concentrations that were several orders of magnitude higher than their Km values for transport in the presence of ATP. The potent uptake blocker reserpine inhibited with a Ki of 340 nM in the absence of ATP, but biphasic inhibition, with Ki values of 3.2 and 345 nM, was observed in the presence of ATP. With incubation times of 24 hr, the potency of reserpine as an inhibitor of binding in the absence of ATP is increased by 1 to 2 orders of magnitude, implying a slow association rate for reserpine in the absence of nucleotide. These results suggest that dihydrotetrabenazine interacts with the catecholamine/serotonin porter in synaptic vesicles, although the binding site is probably not identical to that involved in active transport of substrate.

Volume 30, Issue 3, pp. 252-257, 09/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1986 by the American Society for Pharmacology and Experimental Therapeutics