title: σ-1 Receptor Inhibition of ASIC1a Channels is Dependent on a Pertussis Toxin-Sensitive G-Protein and an AKAP150/Calcineurin Complex.
abstract: ASIC1a channels play a major role in various pathophysiological conditions including depression, anxiety, epilepsy, and neurodegeneration following ischemic stroke. Sigma-1 (σ-1) receptor stimulation depresses the activity of ASIC1a channels in cortical neurons, but the mechanism(s) by which σ-1 receptors exert their influence on ASIC1a remains unknown. Experiments were undertaken to elucidate the signaling cascade linking σ-1 receptors to ASIC1a channels. Immunohistochemical studies showed that σ-1 receptors, ASIC1a and A-kinase anchoring peptide 150 colocalize in the plasma membrane of the cell body and processes of cortical neurons. Fluorometric Ca(2+) imaging experiments showed that disruption of the macromolecular complexes containing AKAP150 diminished the effects of the σ-1 on ASIC1a, as did application of the calcineurin inhibitors, cyclosporin A and FK-506. Moreover, whole-cell patch clamp experiments showed that σ-1 receptors were less effective at decreasing ASIC1a-mediated currents in the presence of the VIVIT peptide, which binds to calcineurin and prevents cellular effects dependent on AKAP150/calcineurin interaction. The coupling of σ-1 to ASIC1a was also disrupted by preincubation of the neurons in the G-protein inhibitor, pertussis toxin (PTX). Taken together, our data reveal that σ-1 receptor block of ASIC1a function is dependent on activation of a PTX-sensitive G-protein and stimulation of AKAP150 bound calcineurin.
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC-9, Tampa, FL, 33612-4799, USA.
authors.forename: Yelenis
authors.initials: Y
authors.lastname: Mari
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC-9, Tampa, FL, 33612-4799, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Katnik
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, 12901 Bruce B. Downs Blvd., MDC-9, Tampa, FL, 33612-4799, USA. jcuevas@health.usf.edu.
authors.forename: Javier
authors.initials: J
authors.lastname: Cuevas
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D037342:Pertussis Toxin / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000097605:Sigma-1 Receptor
chemical_list: D054758:A Kinase Anchor Proteins; D062565:Acid Sensing Ion Channels; D019703:Calcineurin; D002118:Calcium; D037342:Pertussis Toxin; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C415703:Akap5 protein, rat
keywords: AKAP150; ASIC1a; Calcineurin; Sigma-1 receptor