Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.
Level 5 - mechanism / opinion, no new human data
Bench research (X-ray crystallography and in vitro electrophysiology)
PubMed 17882215 · doi:10.1038/nature06163
What was done
The authors determined the crystal structure of a chicken ASIC1 deletion mutant at low pH to 1.9 Angstrom resolution using X-ray crystallography. They also performed electrophysiological experiments on aspartate-to-asparagine point mutants to examine the functional role of acidic amino acid pairs in proton sensing.
What was found
ASIC1 forms a chalice-shaped homotrimer. Each subunit contains short amino and carboxy termini, two transmembrane helices, a bound chloride ion, and an extracellular domain enriched in acidic residues. Carboxyl-carboxylate pairs were observed within 3 Angstroms of each other, consistent with proton sharing. Electrophysiological testing of aspartate-to-asparagine mutants confirmed these pairs participate in proton detection. A disulfide-rich thumb domain bridges the acidic sensing residues and the pore to mediate long-range conformational gating. The abstract reports no numerical electrophysiological values.
Why it matters
This structure establishes the molecular architecture of the ASIC channel family and reveals how extracellular proton binding triggers conformational changes to open the ion channel.
Limits
The findings are from a chicken ASIC1 deletion mutant in vitro rather than full-length human channels in native cellular membranes. The crystal structure captures a static low-pH conformation rather than continuous dynamic transitions across physiological pH ranges.
Cited by
- contradicts At a blood pH of 7.7, pain receptors dissociate into monomeric forms, preventing the trimerized active signaling state and eliminating pain and anxiety signaling in the spinal cord and amygdala.