sigma-1 receptor modulation of acid-sensing ion channel a (ASIC1a) and ASIC1a-induced Ca2+ influx in rat cortical neurons.

Abstract

Acid-sensing ion channels (ASICs) are proton-gated cation channels found in peripheral and central nervous system neurons. The ASIC1a subtype, which has high Ca2+ permeability, is activated by ischemia-induced acidosis and contributes to the neuronal loss that accompanies ischemic stroke. Our laboratory has shown that activation of sigma receptors depresses ion channel activity and [Ca2+](i) dysregulation during ischemia, which enhances neuronal survival. Whole-cell patch-clamp electrophysiology and fluorometric Ca2+ imaging were used to determine whether sigma receptors regulate the function of ASIC in cultured rat cortical neurons. Bath application of the selective ASIC1a blocker, psalmotoxin1, decreased proton-evoked [Ca2+](i) transients and peak membrane currents, suggesting the presence of homomeric ASIC1a channels. The pan-selective sigma-1/sigma-2 receptor agonists, 1,3-di-o-tolyl-guanidine (100 microM) and opipramol (10 microM), reversibly decreased acid-induced elevations in [Ca2+](i) and membrane currents. Pharmacological experiments using sigma receptor-subtype-specific agonists demonstrated that sigma-1, but not sigma-2, receptors inhibit ASIC1a-induced Ca2+ elevations. These results were confirmed using the irreversible sigma receptor antagonist metaphit (50 microM) and the selective sigma-1 antagonist BD1063 (10 nM), which obtunded the inhibitory effects of the sigma-1 agonist, carbetapentane. Activation of ASIC1a was shown to stimulate downstream Ca2+ influx pathways, specifically N-methyl-D-aspartate and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptors and voltage-gated Ca2+ channels. These subsequent Ca2+ influxes were also inhibited upon activation of sigma-1 receptors. These findings demonstrate that sigma-1 receptor stimulation inhibits ASIC1a-mediated membrane currents and consequent intracellular Ca2+ accumulation. The ability to control ionic imbalances and Ca2+ dysregulation evoked by ASIC1a activation makes sigma receptors an attractive target for ischemic stroke therapy.

• Authors: Yelenis Herrera, Christopher Katnik, Jael D Rodriguez, Aaron A Hall, Alison Willing, Keith R Pennypacker, Javier Cuevas
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 327 Issue 2 Pg. 491-502 (Nov 2008) ISSN: 1521-0103 [Electronic] United States
• PMID: 18723775 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acid Sensing Ion Channels
• Calcium Channels
• Cyclopentanes
• Guanidines
• Nerve Tissue Proteins
• PB28 compound
• PcTX1 protein, Psalmopoeus cambridgei
• Peptides
• Piperazines
• Receptors, N-Methyl-D-Aspartate
• Receptors, sigma
• Sodium Channels
• Spider Venoms
• sigma-1 receptor
• carbetapentane
• Tetrodotoxin
• 6-Cyano-7-nitroquinoxaline-2,3-dione
• Dextromethorphan
• 1,3-ditolylguanidine
• Calcium

Topics

• 6-Cyano-7-nitroquinoxaline-2,3-dione (pharmacology)
• Acid Sensing Ion Channels
• Animals
• Calcium (metabolism)
• Calcium Channels (physiology)
• Cerebral Cortex (metabolism)
• Cyclopentanes (pharmacology)
• Dextromethorphan (pharmacology)
• Guanidines (pharmacology)
• Nerve Tissue Proteins (physiology)
• Peptides
• Piperazines (pharmacology)
• Rats
• Receptors, N-Methyl-D-Aspartate (physiology)
• Receptors, sigma (physiology)
• Sodium Channels (physiology)
• Spider Venoms (pharmacology)
• Tetrodotoxin (pharmacology)