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σ-1 Receptor agonist SKF10047 inhibits glutamate release in rat cerebral cortex nerve endings.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2012 May; Vol. 341 (2), pp. 532-42. Date of Electronic Publication: 2012 Feb 22. - Publication Year :
- 2012
-
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.
- Subjects :
- 4-Aminopyridine pharmacology
Amino Acid Transport System X-AG antagonists & inhibitors
Animals
Aspartic Acid pharmacology
Calcium metabolism
Calcium Channel Blockers pharmacology
Calcium Channels metabolism
Calcium Channels, N-Type metabolism
Cytosol drug effects
Cytosol metabolism
Macrolides pharmacology
Male
Membrane Potentials drug effects
Mitochondria drug effects
Mitochondria metabolism
Phenazocine pharmacology
Phosphorylation drug effects
Potassium Channel Blockers pharmacology
Potassium Channels metabolism
Protein Kinase C antagonists & inhibitors
Rats
Rats, Sprague-Dawley
Ryanodine Receptor Calcium Release Channel metabolism
Sodium-Calcium Exchanger metabolism
Vesicular Transport Proteins antagonists & inhibitors
Vesicular Transport Proteins metabolism
Sigma-1 Receptor
Cerebral Cortex drug effects
Cerebral Cortex metabolism
Glutamic Acid metabolism
Nerve Endings drug effects
Nerve Endings metabolism
Phenazocine analogs & derivatives
Receptors, sigma agonists
Receptors, sigma metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 341
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 22357973
- Full Text :
- https://doi.org/10.1124/jpet.111.191189