[1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol, an indole-3-carbinol derivative, inhibits glutamate release in rat cerebrocortical nerve terminals by suppressing the P/Q-type Ca2+ channels and Ca2+/calmodulin/protein kinase A pathway. (November 2020)

• Record Type: Journal Article
• Authors: Lu, Cheng Wei; Lin, Tzu-Yu; Yang, Hsiao Ching; Hung, Chi Feng; Weng, Jing Ru; Chang, Der Chen; Wang, Su Jane
• Is Part Of: Neurochemistry international. Volume 140(2020)
• Publication Date: 2020-11
• Subjects: CIM -- Glutamate release -- P/Q-type Ca2+ channel -- Calmodulin -- PKA -- Synaptosome; I3C Indole-3-carbinol -- CIM [1(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol -- 4-AP 4-aminopyridine -- EGTA ethylene glycol bis(β-aminoethyl ether)-N, N, N1, N1-tetraacetic acid -- DL-TBOA DL-threo-beta-benzyl-oxyaspartate -- CGP37157 7-chloro-5-(2-chlorophenyl)-1, 5-dihydro-4, 1-benzothiazepin-2(3H)-one -- H89 N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide -- ω-CgTX GVIA ω-conotoxin GVIA -- ω-Aga IVA ω-agatoxin IVA -- Fura-2-AM fura-2-acetoxymethyl ester -- CNS central nervous system -- PKA protein kinase A -- [Ca2+]i, intraterminal Ca2+ concentration -- AC adenylate cyclase -- cAMP cyclic adenosine monophosphate -- VDCC voltage-dependent Ca2+ channel; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2020.104845
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Indole-3-carbinol (I3C), found in cruciferous vegetables, has been proposed to exhibit neuroprotective effects. This study aimed to investigate the effect of the I3C derivative [1(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (CIM), which has superior pharmacokinetic properties to I3C, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). We observed that CIM dose-dependently inhibited glutamate release evoked by the potassium channel blocker 4-aminopyridine (4-AP). CIM-mediated inhibition of glutamate release was attributed to reduced exocytosis, as it correlated with the removal of extracellular calcium and blocking of the vesicular glutamate transporter but not the glutamate transporter. In addition, CIM decreased 4-AP-evoked intrasynaptosomal Ca 2+ elevation; however, it did not alter the synaptosomal membrane potential. The inhibition of P/Q-typeCa 2+ channels abolished the effect of CIM on 4-AP-evoked glutamate release, and the effect was not prevented by intracellular Ca 2+ release inhibitors. Moreover, the molecular docking study showed that CIM exhibited the highest binding affinity with the P/Q-type Ca 2+ channels. Finally, the CIM-mediated inhibition of glutamate release was sensitive to calmodulin, adenylate cyclase (AC), and protein kinase A (PKA) inhibitors. Based on these results, we propose that CIM, through the direct suppression of P/Q-type Ca 2+ channels, decreases Ca 2+ influx and the activation of Ca 2+ /calmodulin/AC/PKA signaling, thereby inhibiting glutamate release. This finding is crucial for understanding the role of CIM in the central nervous system and for exploiting its potential in therapeutic interventions. Highlights: The indole-3-carbinol derivative CIM inhibits glutamate release in rat synaptosomes. Reduced Ca 2+ influx through P/Q-type Ca 2+ channels is involved. Suppressed Ca 2+ /calmodulin/PKA participates in achieving the effect. This is the first report of an action of CIM on the central glutamate system.