Key result
C77304 acts as a bifunctional modulator of the proton-activated chloride (PAC) channel, revealing a protonation-independent voltage activation mechanism and identifying E181, E257, and E261 as primary proton sensors.
Why the study?
The proton-activated chloride channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive.
The study unveils the polymodal gating and proton-sensing mechanisms of the PAC channel, identifying key residues for proton sensing and a novel bifunctional modulator, which may inspire future drug development.
No immediate clinical implications; leaves open PAC channel targeting for future cardiovascular research.
The proton-activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we investigated the gating of PAC channels using its novel bifunctional modulator C77304. C77304 acted as a weak activator of the PAC channel, causing moderate activation by acting on its proton gating. However, at higher concentrations, C77304 acted as a weak inhibitor, suppressing channel activity. This dual function was achieved by interacting with 2 modulatory sites of the channel, each with different affinities and dependencies on the channel's state. Moreover, we discovered a protonation-independent voltage activation of the PAC channel that appears to operate through an ion-flux gating mechanism. Through scanning-mutagenesis and molecular dynamics simulation, we confirmed that E181, E257, and E261 in the human PAC channel serve as primary proton sensors, as their alanine mutations eliminated the channel's proton gating while sparing the voltage-dependent gating. This proton-sensing mechanism was conserved among orthologous PAC channels from different species. Collectively, our data unveils the polymodal gating and proton-sensing mechanisms in the PAC channel that may inspire potential drug development.
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Zhao et al. (2023) studied this question. C77304 vs. Vehicle/Control was evaluated on PAC channel currents. C77304 acts as a bifunctional modulator of the proton-activated chloride (PAC) channel, revealing a protonation-independent voltage activation mechanism and identifying E181, E257, and E261 as primary proton sensors.
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