Two-pore domain potassium (K₂P) channels are responsible for maintaining the background conductance essential to the resting membrane potential¹. K₂P channels assemble as dimers containing two pore-forming domains and four transmembrane segments per subunits. Two fenestrations connect the lipid membrane with the central conduction cavity, which can be open or closed depending of the movements of helix TM4². TALK subfamily of K₂P channels is activated by alkaline extracellular pH and is formed by 3 members: TALK-1, TALK-2 and TASK-2. TASK-2 is also gated by intracellular pH (pH_i), being closed by intracellular acidification and activated by increasing pH_i. The neutralization of lysine positioned at the end of TM4 helix, and probably within the fenestrations, by a mutation to K245A abolishes pH_i-gating³. The molecular mechanism by which pH_i-sensing K245 exerts its gating role is unknown. A possible mechanism suggest that K245 protonated is able to open the fenestrations and therefore close the channel⁴. Through computational studies, we modeled the 3D structure of TASK-2 channel in both fenestration states, these models were used as a starting point to perform molecular dynamics simulations. The trajectories analysis reveals a good agreement between the pK_1/2 of K245 obtained experimentally and the pK_a predicted when the fenestrations are closed. Besides, we proved that Norfluoxetine compound is a potent blocker of TASK-2 channels and its putative binding site is within the fenestrations.