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 Cav2.2 (N-type) and Cav2.1 (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.
Footnotes
This work was supported by the Far-Eastern Memorial Hospital of Taiwan [Grant FEMH-2011-D-012].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- SKF10047
- [2S-(2α,6α,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol
- BD1047
- N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine
- 4-AP
- 4-aminopyridine
- [Ca2+]C
- cytosolic free Ca2+ concentration
- DiSC3(5)
- 3′,3′,3′-dipropylthiadicarbocyanine iodide
- KB-R7943
- 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea
- dl-TBOA
- dl-threo-β-benzyl-oxy aspartate
- Fura-2-AM
- fura-2-acetoxymethyl ester
- GDH
- glutamate dehydrogenase
- HBM
- HEPES buffer medium
- BSA
- bovine serum albumin
- PTX
- pertussis toxin
- ω-CgTX
- ω-conotoxin
- PKC
- protein kinase C
- PRE084
- 2-(4-morpholinethyl)-1-phenylcyclohexanecarboxylate
- Go6976
- 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile
- GF109203X
- 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl) maleimide
- CGP37157
- 7-chloro-5-(2-chloropheny)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one
- PD98059
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
- VDCC
- voltage-dependent Ca2+ channel
- ANOVA
- analysis of variance.
- Received December 20, 2011.
- Accepted February 21, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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