Recent bioinformatics and high resolution structural determination revealed prokaryotic ancestors to the superfamily of eukaryotic Cys-loop receptors. One of these channels, called GLIC, is proton-activated and may provide advantages to investigating mechanisms underlying activation of Cys-loop receptors. Here, we used all-atom molecular dynamics simulations to uncover a possible mechanism of activation of the GLIC channel. We started with the x-ray structure of GLIC in the open state and subjected it to simulation under normal conditions. During the 10 ns simulation the channel appeared to close. Then we screened the apparent closed structure for the presence of salt-bridges, and compared the result to salt bridges in the original open x-ray structure. We found 14 salt bridges per subunit that were not present in the open structure. We then protonated the corresponding 11 acidic residues, conducted another 10 ns simulation and found that the channel remained open. We then extracted the final structural frames from the two MD simulations and employed single channel current simulations using the coarse-grained Biology Monte Carlo method. The open structure resulted in a significant ionic current, whereas the closed structure exhibited none. Thus, the 11 acidic residues emerge as likely candidates for mediating proton activation of the GLIC channel.