Subunit-dependent cadmium and nickel inhibition of acid-sensing ion channels.
Acid-sensing ion channels (ASIC) are ligand-gated cation channels that are highly expressed in peripheral sensory and central neurons. ASIC are transiently activated by decreases in extracellular pH and are thought to play important roles in sensory perception, neuronal transmission, and excitability, and in the pathology of neurological conditions, such as brain ischemia. We demonstrate here that the heavy metals Ni(2+) and Cd(2+) dose-dependently inhibit ASIC currents in hippocampus CA1 neurons and in Chinese hamster ovary (CHO) cells heterologously expressing these channels. The effects of both Ni(2+) and Cd(2+) were voltage-independent, fast, and reversible. Neither metal affected activation and desensitization kinetics but rather decreased pH-sensitivity. Moreover, distinct ASIC isoforms were differentially inhibited by Ni(2+) and Cd(2+). External application of 1 mM Ni(2+) rapidly inhibited homomeric ASIC1a and heteromeric ASIC1a/2a channels without affecting ASIC1b, 2a, and ASIC3 homomeric channels and ASIC1a/3 and 2a/3 heteromeric channels. In contrast, external Cd(+) (1 mM) inhibited ASIC2a and ASIC3 homomeric channels and ASIC1a/2a, 1a/3, and 2a/3 heteromeric channels but not ASIC1a homomeric channels. The acid-sensing current in isolated rat hippocampus CA1 neurons, thought to be carried primarily by ASIC1a and 1a/2a, was inhibited by 1 mM Ni(2+). The current study identifies ASIC as a novel target for the neurotoxic heavy metals Cd(2+) and Ni(2+).
Staruschenko
Alexander
A
Department of Physiology, University of Texas Health Science Center at San Antonio, USA. starushchenk@uthscsa.edu
Dorofeeva
Natalia A
NA
Bolshakov
Konstantin V
KV
Stockand
James D
JD
D062565:Acid Sensing Ion Channels; D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D002104:Cadmium / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D008565:Membrane Proteins / Q000187:drug effects* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D009532:Nickel / Q000494:pharmacology*; D018408:Patch-Clamp Techniques / Q000379:methods; D021122:Protein Subunits / Q000502:physiology; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology
C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D015222:Sodium Channels; D002104:Cadmium; D009532:Nickel