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NEUROPHARMACOLOGY

-1 Receptor Modulation of Acid-Sensing Ion Channel a (ASIC1a) and ASIC1a-Induced Ca²⁺ Influx in Rat Cortical Neurons

Department of Molecular Pharmacology and Physiology (Y.H., C.K., J.D.R., A.A.H., A.W., K.R.P., J.C.) and Center for Aging and Brain Repair (A.W.), University of South Florida, College of Medicine, Tampa, Florida

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 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 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 -1/-2 receptor agonists, 1,3-di-o-tolyl-guanidine (100 µM) and opipramol (10 µM), reversibly decreased acid-induced elevations in [Ca²⁺]_i and membrane currents. Pharmacological experiments using receptor-subtype-specific agonists demonstrated that -1, but not -2, receptors inhibit ASIC1a-induced Ca²⁺ elevations. These results were confirmed using the irreversible receptor antagonist metaphit (50 µM) and the selective -1 antagonist BD1063 (10 nM), which obtunded the inhibitory effects of the -1 agonist, carbetapentane. Activation of ASIC1a was shown to stimulate downstream Ca²⁺ influx pathways, specifically N-methyl-D-aspartate and (±)--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 -1 receptors. These findings demonstrate that -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 receptors an attractive target for ischemic stroke therapy.

Address correspondence to: Dr. Javier Cuevas, Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC-9, Tampa, FL 33612-4799. E-mail: jcuevas{at}health.usf.edu

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