TRESK tandem pore potassium (K₂P) channels mainly expressed in the spinal cord, share only 13.5–19.7 % amino acid identity with other K₂P channels. In the mouse and human genome only a single TRESK isoform is present. The unusually low amino acid identity of 65% between the two species orthologues predicts that their funtional properties may also be altered (see also Keshavaprasad et al., 2005). Pharmacological profiling indeed indicates that regulation by arachidonic acid, intracellular Ca²⁺ and extracellular pH varies substantially between mouse and human TRESK channels. In investigating acid sensitivity extracellular acidification to pH 6.0 reduces channel activity of mouse TRESK to 40±13% (n=9) with a halfmaximal inhibition at pH 6.9. In contrast, human TRESK is insensitive to proton changes within the physiological range from pH 6.0 to pH 8.5. Histidine residues at the extracellular protein surface of K⁺ channels have been considered candidate sensors for outer pH changes (Rajan et al., 2000). Mutating a single histidine at position 132 of mouse TRESK (H132N) leads to a complete loss of pH sensitivity. The vice-versa mutation converts hTRESK (Y121H) into an acid-sensitive channel similar to mTRESK indicating that this residue is necessary and sufficient for this property. Thus, a single residue exchange causes loss of acid sensitivity in human TRESK channels.