Calmidazolium selectively inhibits exocytotic glutamate release evoked by P2X7 receptor activation

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• 作者：Chiara Cervetto^a ; Maria Chiara Mazzotta^a ; Daniela Frattaroli^a ; Susanna Alloisio^b ; Mario Nobile^b ; Guido Maura^a ; ^c ; ^d ; Manuela Marcoli^a ; ^c ; ^{marcoli@pharmatox.unige.it}
• 关键词：A-438079 ; 3-(5-(2 ; 3-dichlorophenyl)-1H-tetrazol-1-yl)-methyl pyridine ; BzATP ; 2&prime ; -3&prime ; -O-(benzoylbenzoyl)ATP ; [Ca2+]i ; intracellular Ca2+ concentration ; P2X7R ; P2X7 receptor ; ROI ; region of interest ; VOCCs ; voltage operated calcium channels
• 刊名：Neurochemistry International
• 出版年：2012
• 期刊代码：120_01970186
• 类别：bio
• 出版时间：June, 2012
• 卷：60
• 期：8
• 页码：768-772
• 文件大小：436 K

摘要

We previously observed that activation of presynaptic P2X7 receptors located on rat cerebrocortical nerve terminals induced the release of glutamate through different modes: the channel conformation allowing Ca²⁺ entry triggered exocytotic release, while the receptor itself functioned as a permeation pathway for the non-exocytotic glutamate release. Considering that exocytotic and non-exocytotic glutamate release evoked by the activation of P2X7 receptors might play a role in the control of glutamatergic synapses, we investigated whether calmidazolium (which has been found to inhibit small cation currents through recombinant P2X7 receptors, but not organic molecule permeation) could distinguish between P2X7-related exocytotic and non-exocytotic modes of glutamate release. We found that calmidazolium inhibited the intrasynaptosomal Ca²⁺ response to P2X7 receptor activation and the Ca²⁺-dependent exocytotic glutamate release from rat cerebrocortical nerve terminals, but was ineffective against the Ca²⁺-independent glutamate release. The P2X7 competitive antagonist A-438079 eliminated both exocytotic and non-exocytotic P2X7 receptor-evoked glutamate release. Selective inhibition of exocytotic glutamate release indicates that calmidazolium inhibits events dependent on the function of native rat P2X7 receptors as Ca²⁺ channels, and suggests that it can be used as a tool to dissociate P2X7-evoked exocytotic from non-exocytotic glutamate release.