Presynaptic malfunction: the neurotoxic effects of cadmium and lead on the proton gradient of synaptic vesicles and glutamate transport |
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Authors: | Borisova Tatiana Krisanova Natalia Sivko Roman Kasatkina Ludmila Borysov Arseniy Griffin Susan Wireman Mike |
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Institution: | a The Department of Neurochemistry, Palladin Institute of Biochemistry, NAS of Ukraine, 9 Leontovicha Street, Kiev 01601, Ukraine b U.S. Environmental Protection Agency, 1595, Wynkoop Street, Denver, CO 80202-1129, USA |
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Abstract: | Exposure to Cd2+ and Pb2+ has neurotoxic consequences for human health and may cause neurodegeneration. The study focused on the analysis of the presynaptic mechanisms underlying the neurotoxic effects of non-essential heavy metals Cd2+ and Pb2+. It was shown that the preincubation of rat brain nerve terminals with Cd2+ (200 μM) or Pb2+ (200 μM) resulted in the attenuation of synaptic vesicles acidification, which was assessed by the steady state level of the fluorescence of pH-sensitive dye acridine orange. A decrease in l-14C]glutamate accumulation in digitonin-permeabilized synaptosomes after the addition of the metals, which reflected lowered l-14C]glutamate accumulation by synaptic vesicles inside of synaptosomes, may be considered in the support of the above data. Using isolated rat brain synaptic vesicles, it was found that 50 μM Cd2+ or Pb2+ caused dissipation of their proton gradient, whereas the application of essential heavy metal Mn2+ did not do it within the range of the concentration of 50-500 μM. Thus, synaptic malfunction associated with the influence of Cd2+ and Pb2+ may result from partial dissipation of the synaptic vesicle proton gradient that leads to: (1) a decrease in stimulated exocytosis, which is associated not only with the blockage of voltage-gated Ca2+ channels, but also with incomplete filling of synaptic vesicles; (2) an attenuation of Na+-dependent glutamate uptake. |
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Keywords: | ΔμH+ synaptic vesicle electrochemical H+ gradient V-ATPase vesicular ATPase DCT1 divalent сation/metal ion transporter CNS central nervous system |
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