Gating ASICs

Acid-sensing ion channels (ASICs) are members of a family of cation-selective ion channels that includes epithelial sodium channels and the degenerins, which shows a remarkable diversity of function and in the mechanisms of activation (see Canessa). Implicated in sensory perception, ASICs are sodium-selective and activated by extracellular protons independently of membrane potential. Jasti et al . combined crystallographic analysis with electrophysiology to explore the low-pH structure of ΔASIC1, a chicken ASIC deletion mutant (in a desensitized nonconducting state), and investigated the mechanism underlying its pH-dependent gating. Unexpectedly, they found that ΔASIC1 formed a homotrimer. Each subunit had two transmembrane helices and a large extracellular domain. Describing the overall domain structure of ΔASIC1 subunits as resembling an "upright forearm and clenched hand" (with the extracellular domain constituting the "hand"), the authors identified a group of acidic residues as proton-binding sites that constitute the pH sensor. They suggest that proton binding leads to movement of the disulfide-rich thumb region, which transmits a long-range conformational change to allow the channel to open. J. Jasti, H. Furukawa, E. B. Gonzales, E. Gouaux, Structure of acid-sensing ion channel 1 at 1.9 Å resolution and low pH. Nature 449 , 316-323 (2007). [PubMed] C. M. Canessa, Unexpected opening. Nature 449 , 293-294 (2007). [PubMed]