Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels.
Acid-sensing ion channels (ASICs), a novel class of ligand-gated cation channels activated by protons, are highly expressed in peripheral sensory and central neurons. Activation of ASICs may play an important role in physiological processes such as nociception, mechanosensation, and learning-memory, and in the pathology of neurological conditions such as brain ischemia. Modulation of the activities of ASICs is expected to have a significant influence on the roles that these channels can play in both physiological and/or pathological processes. Here we show that the divalent cation Zn2+, an endogenous trace element, dose-dependently inhibits ASIC currents in cultured mouse cortical neurons at nanomolar concentrations. With ASICs expressed in Chinese hamster ovary cells, Zn2+ inhibits currents mediated by homomeric ASIC1a and heteromeric ASIC1a-ASIC2a channels, without affecting currents mediated by homomeric ASIC1beta, ASIC2a, or ASIC3. Consistent with ASIC1a-specific modulation, high-affinity Zn2+ inhibition is absent in neurons from ASIC1a knock-out mice. Current-clamp recordings and Ca2+-imaging experiments demonstrated that Zn2+ inhibits acid-induced membrane depolarization and the increase of intracellular Ca2+. Mutation of lysine-133 in the extracellular domain of the ASIC1a subunit abolishes the high-affinity Zn2+ inhibition. Our studies suggest that Zn2+ may play an important role in a negative feedback system for preventing overexcitation of neurons during normal synaptic transmission and ASIC1a-mediated excitotoxicity in pathological conditions.
Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA.
Xiang-Ping
XP
Chu
John A
JA
Wemmie
Wei-Zhen
WZ
Wang
Xiao-Man
XM
Zhu
Julie A
JA
Saugstad
Margaret P
MP
Price
Roger P
RP
Simon
Zhi-Gang
ZG
Xiong
D062565:Acid Sensing Ion Channels; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002614:Chelating Agents / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004553:Electric Conductivity; D006863:Hydrogen-Ion Concentration; D008239:Lysine / Q000235:genetics; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics; D015032:Zinc / Q000494:pharmacology*
C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D002614:Chelating Agents; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D015222:Sodium Channels; D015032:Zinc; D008239:Lysine; D002118:Calcium