Subunit-dependent cadmium and nickel inhibition of acid-sensing ion channels

Alexander Staruschenko, Natalia A. Dorofeeva, Konstantin V. Bolshakov, James D. Stockand

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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 Ni2+ and Cd2+ dose-dependently inhibit ASIC currents in hippocampus CA1 neurons and in Chinese hamster ovary (CHO) cells heterologously expressing these channels. The effects of both Ni2+ and Cd2+ 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 Ni2+ and Cd2+. External application of 1 mM Ni2+ 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 Cd2+ (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 Ni2+. The current study identifies ASIC as a novel target for the neurotoxic heavy metals Cd2+ and Ni2+.

Original languageEnglish (US)
Pages (from-to)97-107
Number of pages11
JournalDevelopmental Neurobiology
Volume67
Issue number1
DOIs
StatePublished - Jan 2007

Keywords

  • ASIC
  • Acid-sensing ion channels
  • Cadmium
  • Nickel
  • Proton-gated channels

ASJC Scopus subject areas

  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience

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