TY - JOUR TI - Kinetic analysis of ASIC1a delineates conformational signaling from proton-sensing domains to the channel gate AU - Vullo, Sabrina AU - Ambrosio, Nicolas AU - Kucera, Jan P AU - Bignucolo, Olivier AU - Kellenberger, Stephan A2 - Islas, Leon D A2 - Swartz, Kenton J A2 - Islas, Leon D A2 - Bankston, John A2 - Cowgill, John B VL - 10 PY - 2021 DA - 2021/03/17 SP - e66488 C1 - eLife 2021;10:e66488 DO - 10.7554/eLife.66488 UR - https://doi.org/10.7554/eLife.66488 AB - Acid-sensing ion channels (ASICs) are neuronal Na+ channels that are activated by a drop in pH. Their established physiological and pathological roles, involving fear behaviors, learning, pain sensation, and neurodegeneration after stroke, make them promising targets for future drugs. Currently, the ASIC activation mechanism is not understood. Here, we used voltage-clamp fluorometry (VCF) combined with fluorophore-quencher pairing to determine the kinetics and direction of movements. We show that conformational changes with the speed of channel activation occur close to the gate and in more distant extracellular sites, where they may be driven by local protonation events. Further, we provide evidence for fast conformational changes in a pathway linking protonation sites to the channel pore, in which an extracellular interdomain loop interacts via aromatic residue interactions with the upper end of a transmembrane helix and would thereby open the gate. KW - conformational change KW - ion channel KW - voltage-clamp fluorometry KW - molecular dynamics KW - kinetic model JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -