title: Calcium-permeable acid-sensing ion channel is a molecular target of the neurotoxic metal ion lead.
abstract: Acid-sensing ion channels (ASICs) are emerging as fundamental players in the regulation of neural plasticity and in pathological conditions. Here we showed that lead (Pb2+), a well known neurotoxic metal ion, reversibly and concentration-dependently inhibited ASIC currents in the acutely dissociated spinal dorsal horn and hippocampal CA1 neurons of rats. In vitro expression of ASIC subunits in combination demonstrated that both ASIC1 and -3 subunits were sensitive to Pb2+. Mechanistically, Pb2+ reduced the pH sensitivity of ASICs independent of membrane voltage change. Moreover, Pb2+ inhibited the ASIC-mediated membrane depolarization and the elevation of intracellular Ca2+ concentration. In addition, we compared the effect of Pb2+ with that of Ca2+ or amiloride to explore the possible interactions of Pb2+ and Ca2+ in regulating ASICs, and we found that Pb2+ inhibited ASIC currents independent of the amiloride/Ca2+ blockade. Because ASIC1b and -3 subunits are mainly expressed in peripheral neurons, our data identified ASIC1a-containing Ca2+-permeable ASIC as a novel central target of Pb2+ action, which may contribute to Pb2+ neurotoxicity.
authors.affiliation: Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Duan
authors.forename: Han
authors.initials: H
authors.lastname: Xu
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Tian-Le
authors.initials: TL
authors.lastname: Xu
mesh_terms: D062565:Acid Sensing Ion Channels; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D007854:Lead / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000378:metabolism; D009676:Noxae / Q000494:pharmacology; D020671:Posterior Horn Cells / Q000378:metabolism; D021122:Protein Subunits; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels
chemical_list: D062565:Acid Sensing Ion Channels; C568268:Asic1 protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009676:Noxae; D021122:Protein Subunits; D015222:Sodium Channels; D007854:Lead; D000584:Amiloride; D002118:Calcium