Energy-dependent accumulation of neuron blockers causes selective inhibition of neurotransmitter uptake by brain synaptic vesicles.
The effects of neuron blockers on neurotransmitter accumulation in synaptic vesicles were investigated. Upon addition of ATP, brain synaptic vesicles accumulated chlorpromazine, haloperidol, and propranolol against concentration gradients of more than 100-fold. Bioenergetic analysis indicated that the transmembrane pH gradient (delta pH) established by the vacuolar-type H(+)-ATPase is a direct driving force for these uptakes. Essentially the same results were obtained with vesicles from bovine adrenal chromaffin granules and proteoliposomes reconstituted with purified vacuolar H(+)-ATPase, indicating that the energy-dependent accumulation is due to diffusion and does not involve transport carriers specific for the blockers. Incubations of the two organelles with the blockers resulted in dissipation of delta pH and slight increase of membrane potential (delta psi) without affecting ATPase activity. Under the same conditions, uptake of dopamine or gamma-aminobutyrate (delta pH-driven transport) was inhibited by neuron blockers, whereas uptake of glutamate (delta psi-driven transport) was slightly stimulated. Thus, neuron blockers inhibited delta pH-driven uptake of neurotransmitter by dissipating the driving force. These results strongly suggest that synaptic vesicles are one of the target sites of neuron blockers.
Moriyama
Y
Y
Department of Biochemistry and Organic Chemistry, Osaka University, Japan.
Tsai
H L
HL
Futai
M
M
D000818:Animals; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism*; D002746:Chlorpromazine / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D006220:Haloperidol / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008297:Male; D009474:Neurons / Q000187:drug effects*; D011433:Propranolol / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013572:Synaptic Vesicles / Q000378:metabolism*
D005971:Glutamates; D011433:Propranolol; D006180:Proton-Translocating ATPases; D006220:Haloperidol; D002746:Chlorpromazine; D004298:Dopamine