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Zinc inhibits glutamate release via activation of pre‐synaptic K ATP channels and reduces ischaemic damage in rat hippocampus
Author(s) -
Bancila Victor,
Nikonenko Irina,
Dunant Yves,
Bloc Alain
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02587.x
Subject(s) - diazoxide , glutamate receptor , tolbutamide , chemistry , hippocampal formation , nmda receptor , neurotransmission , excitatory postsynaptic potential , potassium channel , biophysics , hippocampus , pharmacology , neuroscience , biochemistry , biology , endocrinology , receptor , insulin
Zinc is concentrated in certain CNS excitatory tracts, especially in hippocampal mossy fibres where it has been suggested to modulate synaptic transmission and plasticity. Using rat mossy fibre synaptosomes depolarized by 4‐aminopyridine, we show here that low zinc concentrations restore the membrane potential and reduce glutamate release. Both effects arose from activation of ATP‐sensitive potassium channels (K ATP ), since they were mimicked by the K ATP opener diazoxide and antagonized by the K ATP blocker tolbutamide. Using recombinant channels expressed in COS‐7 cells, we confirmed that micromolar zinc did activate K ATP of the type found in hippocampus. We tested the hypothesis that this action of zinc could be beneficial during an ischaemic challenge by using organotypic hippocampal slice cultures. When zinc was applied at micromolar concentrations during a brief anoxic‐hypoglycaemic episode, it significantly attenuated the ensuing neuronal death, whereas chelation of endogenous zinc markedly aggravated cell damage. Protective effect of zinc was mediated through K ATP , as was shown by using the opener diazoxide and the blocker tolbutamide. Thus, by activating pre‐synaptic K ATP channels, zinc protects neurones from hyper‐excitation, excessive transmitter release and exitotoxicity, and may thus act as an endogenous neuroprotector in conditions such as epilepsy or stroke.