The pH dependence of the TASK channel sub-family is at least partly regulated by protonation of the side chain of a histidine residue (H98) which lies just beyond the consensus sequence for K⁺ selectivity in P1 (Kim et al. 2000; Ashmole et al. 2001). Previously we have reported that mutation of other residues located both inside the pore region e.g. isoleucine 94 in TASK-3 (Johnson et al. 2004) and outside e.g. glutamate 182 in TASK-1 (Ashmole et al. 2004) results in TASK channels with reduced sensitivity to extracellular pH. However, these channels also have significantly increased permeability to Rb⁺ and Na⁺ suggesting some disruption to the selectivity filter. Here we report the effect on ionic selectivity and pH sensitivity of mutation of a conserved alanine (A) residue, A237 (de la Cruz et al. 2003), located distal to the selectivity filter, at the cytoplasmic end of transmembrane domain M4. Murine TASK-1 channels were expressed in oocytes taken from Xenopus frogs that had been anaesthetised by immersion in 0.3% w/v MS222 and killed by destruction of the brain and spinal cord. We used two-electrode voltage clamp to investigate ionic selectivity and pH sensitivity. Ionic selectivity was calculated by measuring the shift in reversal potential when K⁺ in the external medium was replaced by Rb⁺ or Na⁺. The mutation A237T had no effect on channel selectivity. In oocytes expressing wild type channels PRb/PK was 0.77 ± 0.02 (n = 9; mean ± SEM) and PNa/PK was 0.04 ± 0.003 (n = 16). For A237T neither the PRb/PK of 0.79 ± 0.02 (n = 5) nor the PNa/PK of 0.05 ± 0.004 (n = 5) was significantly different to wild type (ANOVA) indicating that the selectivity filter of the mutant channel remains intact. Remarkably however the mutant channels showed no sensitivity to extracellular pH over the physiological range. Whereas wild type channels are largely shut at pH6, mutant channels remain open. This effect is most striking at positive membrane potentials; at +100mV IK(pH6)/IK(pH8.5) = 0.99 ± 0.03 (n = 7). Even at −100mV, IK(pH6)/IK(pH8.5) = 0.88 ± 0.04 (n = 7). Our results show that the response to acidification of TASK-1 cannot simply be due to channel blockage by protonation of the histidine (H98) side chain but rather must involve a gating process.