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

The acid-sensing ion channel (ASIC) subunits ASIC1, ASIC2, and ASIC3 are me mbers of the amiloride-sensitive Na+ channel/degenerin family of ion channe ls. They form proton-gated channels that are expressed in the central nervo us system and in sensory neurons, where they are thought to play an importa nt role in pain accompanying tissue acidosis, A splice variant of ASIC2, AS IC2b, is not active on its own but modifies the properties of ASIC3, In par ticular, whereas most members of the amiloride-sensitive Na+ channel/degene rin family are highly selective for Na+ over K+, ASIC3/ASIC2b heteromultime rs show a nonselective component, Chimeras of the two splice variants allow ed identification of a 9-amino acid region preceding the first transmembran e (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 muta ted 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 (T2 6K) also has modified Na+ selectivity. Our results suggest that the pre-TM1 region of ASICs participates in the ion pore.