title: σ-1 Receptor agonist SKF10047 inhibits glutamate release in rat cerebral cortex nerve endings.
abstract: σ-1 Receptors are expressed in the brain, and their activation has been shown to prevent neuronal death associated with glutamate toxicity. This study investigates the possible mechanism and effect of [2S-(2α,6α,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol (SKF10047), a σ-1 receptor agonist, on endogenous glutamate release in the nerve terminals of rat cerebral cortex. Results show that SKF10047 inhibited the release of glutamate evoked by the K⁺ channel blocker 4-aminopyridine (4-AP), and the σ-1 receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) blocked this phenomenon. The effects of SKF10047 on the evoked glutamate release were prevented by the chelating extracellular Ca²⁺ions and the vesicular transporter inhibitor bafilomycin A1. However, the glutamate transporter inhibitor DL-threo-β-benzyl-oxyaspartate did not have any effect on the action of SKF10047. SKF10047 decreased the depolarization-induced increase in the cytosolic free Ca²⁺ concentration ([Ca²⁺](C)), but did not alter 4-AP-mediated depolarization. Furthermore, the effects of SKF10047 on evoked glutamate release were prevented by blocking the Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) channels, but not by blocking the ryanodine receptors or the mitochondrial Na⁺/Ca²⁺ exchange. In addition, conventional protein kinase C (PKC) inhibitors abolished the SKF10047 effect on 4-AP-evoked glutamate release. Western blot analyses showed that SKF10047 decreased the 4-AP-induced phosphorylation of PKC and PKCα. These results show that σ-1 receptor activation inhibits glutamate release from rat cortical nerve terminals. This effect is linked to a decrease in [Ca²⁺](C) caused by Ca²⁺ entry through presynaptic voltage-dependent Ca²⁺ channels and the suppression of the PKC signaling cascade.
authors.affiliation: Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei, Taiwan.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Lu
authors.forename: Tzu-Yu
authors.initials: TY
authors.lastname: Lin
authors.forename: Chia-Chuan
authors.initials: CC
authors.lastname: Wang
authors.forename: Su-Jane
authors.initials: SJ
authors.lastname: Wang
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009411:Nerve Endings / Q000187:drug effects* / Q000378:metabolism*; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D015761:4-Aminopyridine; D027322:Amino Acid Transport System X-AG; D001224:Aspartic Acid; D002118:Calcium; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D018698:Glutamic Acid; D018942:Macrolides; D010620:Phenazocine; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011493:Protein Kinase C; D017480:Receptors, sigma; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D033921:Vesicular Transport Proteins; D000097605:Sigma-1 Receptor; C503279:Cacna1b protein, rat; C120673:benzyloxyaspartate; C012134:SK&F 10047; C040929:bafilomycin A1