Structure of acid-sensing ion channel 1 at 1.9 Å resolution and low pH

Acid-sensing ion channels (ASICs) are voltage-independent, proton-activated receptors that belong to the epithelial sodium channel/degenerin family of ion channels and are implicated in perception of pain, ischaemic stroke, mechanosensation, learning and memory. Here we report the low-pH crystal structure of a chicken ASIC1 deletion mutant at 1.9 Å resolution. Each subunit of the chalice-shaped homotrimer is composed of short amino and carboxy termini, two transmembrane helices, a bound chloride ion and a disulphide-rich, multidomain extracellular region enriched in acidic residues and carboxyl-carboxylate pairs within 3 Å, suggesting that at least one carboxyl group bears a proton. Electrophysiological studies on aspartate-to-asparagine mutants confirm that these carboxyl-carboxylate pairs participate in proton sensing. Between the acidic residues and the transmembrane pore lies a disulphide-rich ‘thumb’ domain poised to couple the binding of protons to the opening of the ion channel, thus demonstrating that proton activation involves long-range conformational changes. Sensing acid Acid-sensing ion channels (ASICs) are proton-activated receptors that are present in many human tissues and organs, and are particularly abundant in the central and peripheral nervous system. In experiments in mice they have been implicated in pain sensation and fear-conditioned learning. They are members of a superfamily of receptors that participates in a broad range of biological activities, from maintenance of sodium homeostasis to mechanosensation. Until now, though, the structure of this important class of proteins was unknown. Now a paper from Eric Gouaux's lab reports the high-resolution crystal structure of chicken ASIC1 in the closed state. Unlike any other channel so far examined, it is a trimer. Its large extracellular component — represented by the top 'half' of the cover image where the bars represent the membrane — is rich in cavities and protrusions and contains pairs of acidic residues involved in proton sensing. Acid-sensing ion channels belong to a large family of ion channels, the diverse functions of which range from sodium absorption to mechanosensitivity; however, the structure of this class of proteins is unknown. Here, the high-resolution crystal structure of chicken ASIC1 in the closed state is reported, and of note is the trimeric architecture and the appealing mechanism of proton-gating proposed.