A combined computational and functional approach identifies new residues involved in pH-dependent gating of ASIC1a.

摘要: Acid-sensing ion channels (ASICs) are key receptors for extracellular protons. These neuronal nonvoltage-gated Na+ involved in learning, the expression of fear, neurodegeneration after ischemia, and pain sensation. We have applied a systematic approach to identify potential pH sensors ASIC1a elucidate mechanisms by which variations govern ASIC gating. first calculated pKa value all His, Glu, Asp residues using Poisson-Boltzmann continuum approach, based on three-dimensional structure, candidate pH-sensing residues. The role these was then assessed site-directed mutagenesis chemical modification, combined with functional analysis. localization putative suggests that changes control gating protonation/deprotonation many per subunit different channel domains. Analysis function palm domain close central vertical axis allowed prediction conformational this region during Our study provides basis intrinsic dependence describes an can also be investigation other proteins.