Conformational plasticity of human acid-sensing ion channel 1a

Acid-sensing ion channels (ASICs) are typically activated by acidic environments and contribute to nociception and synaptic plasticity. ASIC1a is the most abundant subunit in the central nervous system and forms homomeric channels permeable to Na+ and Ca2+, making it a compelling therapeutic target for acidotic pathologies including stroke and traumatic brain injury. However, a complete conformational library of human ASIC1a in its various functional states has yet to be described. Using cryo-EM, we obtained hASIC1a structures across a pH range between 8.5 and 5.7, as well as in the presence of a toxin agonist and a gating-modulating mutation. We identify six major conformations that establish linear transmembrane helices to be associated with an open state, delineate mechanistic differences between proton and toxin activation, and demonstrate that desensitization leads to unexpected conformational diversity in the transmembrane domain. Together, they provide a three-dimensional rationalization of decades of structure-function studies on ASIC.