title: Functional modifications of acid-sensing ion channels by ligand-gated chloride channels.
abstract: Together, acid-sensing ion channels (ASICs) and epithelial sodium channels (ENaC) constitute the majority of voltage-independent sodium channels in mammals. ENaC is regulated by a chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show that ASICs were reversibly inhibited by activation of GABA(A) receptors in murine hippocampal neurons. This inhibition of ASICs required opening of the chloride channels but occurred with both outward and inward GABA(A) receptor-mediated currents. Moreover, activation of the GABA(A) receptors modified the pharmacological features and kinetic properties of the ASIC currents, including the time course of activation, desensitization and deactivation. Modification of ASICs by open GABA(A) receptors was also observed in both nucleated patches and outside-out patches excised from hippocampal neurons. Interestingly, ASICs and GABA(A) receptors interacted to regulate synaptic plasticity in CA1 hippocampal slices. The activation of glycine receptors, which are similar to GABA(A) receptors, also modified ASICs in spinal neurons. We conclude that GABA(A) receptors and glycine receptors modify ASICs in neurons through mechanisms that require the opening of chloride channels.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Chen
authors.forename: Paul
authors.initials: P
authors.lastname: Whissell
authors.forename: Beverley A
authors.initials: BA
authors.lastname: Orser
authors.forename: John F
authors.initials: JF
authors.lastname: MacDonald
mesh_terms: D062565:Acid Sensing Ion Channels; D000818:Animals; D018118:Chloride Channels / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D007477:Ions; D007700:Kinetics; D058446:Ligand-Gated Ion Channels / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000378:metabolism; D018009:Receptors, Glycine / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D062565:Acid Sensing Ion Channels; D018118:Chloride Channels; D002712:Chlorides; D007477:Ions; D058446:Ligand-Gated Ion Channels; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D015222:Sodium Channels; D005680:gamma-Aminobutyric Acid