Potent,extra-channel influence of several calcium-channel modulators on striatal binding of [3H]tyramine |
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Authors: | Andrea Vaccari PierLuigi Saba GianLuigi Gessa |
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Institution: | (1) Department of Neuroscience B. Brodie , Via Porcell 4, 09124 Cagliari, Italy |
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Abstract: | A number of Ca2+-, K+-, and Na+-channel modulators has been tested with respect to their effects on 3H]tyramine (TY) binding, as a putative marker for the vesicular dopamine (DA) transporter in striatal membrane preparations containing vesicle ghosts. Among organic Ca2+-channel modulators, the diphenylalkylamines tested consistently inhibited TY binding: the order of potency was prenylamine>lidoflazine>flunarizine>cinnarizine, with Ki values of 0.1, 0.2, 0.5 and 1.2 M, respectively. Low (up to 100 nM) concentrations of prenylamine did competitively inhibit TY binding, and higher concentrations provoked a mixed-type inhibition. Furthermore, LIGAND-analysis of competition curves revealed a high- and a low-affinity binding site for prenylamine and flunarizine. The TY binding process was also sensitive to selected K+- and Na+-channel modulators. Since several Ca2+-antagonists are known to affect H+-ATPase and the bioenergetics of catecholamine storage vesicles in chromaffin granules, thus affecting monoamine storage, the energy requirements for the formation of the TY/carrier complex were here assessed, assuming similarity between chromaffin granules and synaptic vesicles. TY binding, though not reflecting endovesicle-sequestered TY, was indeed strongly sensitive (with Ki coefficients in the fM or low nM range) to the dissipation of the vesicular transmembrane proton concentration ( pH), electrical ( ), and proton electrochemical ( H+) gradients, provoked by a number of specifically targeted agents. It is concluded that Ca2+-channel agents of the diphenylalkylamine group may directly affect striatal TY binding due to an extrachannel-regulated competition with TY for the vesicular carrier of DA, as well indirectly, by disruption of the transmembrane energization of the reserpine-sensitive carrier. |
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Keywords: | [3H]Tyramine binding vesicular markers Ca2+-channel modulators K+-channel antagonists Na+-channel agents dopamine carrier vesicle membrane energetics |
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