Subunit-dependent cadmium and nickel inhibition of acid-sensing ion channels. Dev Neurobiol 2007 Jan;67(1):97-107
Date
04/20/2007Pubmed ID
17443775DOI
10.1002/dneu.20338Scopus ID
2-s2.0-34548605232 (requires institutional sign-in at Scopus site) 50 CitationsAbstract
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+).
Author List
Staruschenko A, Dorofeeva NA, Bolshakov KV, Stockand JDMESH terms used to index this publication - Major topics in bold
Acid Sensing Ion ChannelsAnimals
Animals, Newborn
CHO Cells
Cadmium
Cricetinae
Cricetulus
Dose-Response Relationship, Drug
Hippocampus
Hydrogen-Ion Concentration
In Vitro Techniques
Ion Channel Gating
Membrane Potentials
Membrane Proteins
Nerve Tissue Proteins
Neural Inhibition
Neurons
Nickel
Patch-Clamp Techniques
Protein Subunits
Rats
Sodium Channels