The pre-transmembrane 1 domain of acid-sensing ion channels participates in the ion pore

J Biol Chem. 1999 Apr 9;274(15):10129-32. doi: 10.1074/jbc.274.15.10129.


The acid-sensing ion channel (ASIC) subunits ASIC1, ASIC2, and ASIC3 are members of the amiloride-sensitive Na+ channel/degenerin family of ion channels. They form proton-gated channels that are expressed in the central nervous system and in sensory neurons, where they are thought to play an important role in pain accompanying tissue acidosis. A splice variant of ASIC2, ASIC2b, is not active on its own but modifies the properties of ASIC3. In particular, whereas most members of the amiloride-sensitive Na+ channel/degenerin family are highly selective for Na+ over K+, ASIC3/ASIC2b heteromultimers show a nonselective component. Chimeras of the two splice variants allowed identification of a 9-amino acid region preceding the first transmembrane (TM) domain (pre-TM1) of ASIC2 that is involved in ion permeation and is critical for Na+ selectivity. Three amino acids in this region (Ile-19, Phe-20, and Thr-25) appear to be particularly important, because channels mutated at these residues discriminate poorly between Na+ and K+. In addition, the pH dependences of the activity of the F20S and T25K mutants are changed as compared with that of wild-type ASIC2. A corresponding ASIC3 mutant (T26K) also has modified Na+ selectivity. Our results suggest that the pre-TM1 region of ASICs participates in the ion pore.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Degenerin Sodium Channels
  • Electrophysiology
  • Epithelial Sodium Channels
  • Ion Channels / chemistry*
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Molecular Sequence Data
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Potassium Channels / chemistry*
  • Potassium Channels / genetics
  • Potassium Channels / metabolism
  • Sodium Channels / chemistry*
  • Sodium Channels / genetics
  • Sodium Channels / metabolism


  • Degenerin Sodium Channels
  • Epithelial Sodium Channels
  • Ion Channels
  • Nerve Tissue Proteins
  • Potassium Channels
  • Sodium Channels