sigma-1 receptor modulation of acid-sensing ion channel a (ASIC1a) and ASIC1a-induced Ca2+ influx in rat cortical neurons.
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.
Herrera
Yelenis
Y
Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, FL 33612-4799, USA.
Katnik
Christopher
C
Rodriguez
Jael D
JD
Hall
Aaron A
AA
Willing
Alison
A
Pennypacker
Keith R
KR
Cuevas
Javier
J
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D062565:Acid Sensing Ion Channels; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism*; D003517:Cyclopentanes / Q000494:pharmacology; D003915:Dextromethorphan / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010455:Peptides; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D017480:Receptors, sigma / Q000502:physiology*; D015222:Sodium Channels / Q000502:physiology*; D013111:Spider Venoms / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D000097605:Sigma-1 Receptor
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D062565:Acid Sensing Ion Channels; D002118:Calcium; D015220:Calcium Channels; D003517:Cyclopentanes; D003915:Dextromethorphan; D006146:Guanidines; D009419:Nerve Tissue Proteins; D010455:Peptides; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D015222:Sodium Channels; D013111:Spider Venoms; D013779:Tetrodotoxin; D000097605:Sigma-1 Receptor; C513937:PB28 compound; C413209:PcTX1 protein, Psalmopoeus cambridgei; C018861:carbetapentane; C050232:1,3-ditolylguanidine