Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1

Acid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key participant in channel gating. While binding to this region by the venom peptide psalmotoxin modulates channel gating, molecular and structural mechanisms of ASIC gating modulation by small molecules are poorly understood. Here, combining functional, crystallographic, computational and mutational approaches, we show that two structurally distinct small molecules potently and allosterically inhibit channel activation and desensitization by binding at the acidic pocket and stabilizing the closed state of rat/chicken ASIC1. Our work identifies a previously unidentified binding site, elucidates a molecular mechanism of small molecule modulation of ASIC gating, and demonstrates directly the structural basis of such modulation, providing mechanistic and structural insight into ASIC gating, modulation and therapeutic targeting.

Generation of water window single attosecond pulse from multi-cycle mid-infrared laser field with chirp gating modulation

A potential scheme to produce the water window single attosecond pulses (SAPs) from the multi-cycle mid-infrared (MIR) laser field has been investigated with the help of the chirp gating modulation. It is found that with the introduction of the laser chirp (i.e. up-chirp or down-chirp modulation), the extension of the harmonic cutoff can be achieved and the single harmonic radiation peak (HRP) can be selected during the harmonic emission process. Moreover, the chirp gating modulation on the high-order harmonic generation (HHG) is sensitive to the few-cycle pulse duration, but it is not very sensitive to the multi-cycle pulse duration. Moreover, a larger extension of the harmonic cutoff covering the whole water window region can be found with the help of the multi-cycle down-chirp modulation. Further, by properly choosing the coherent superposition of the ground state and the high Rydberg state as the initial state, the efficiency of HHG can be enhanced by 5 orders of magnitude. Finally, a series of high-intensity sub-40as pulses covering the water window region can be obtained.