TASK3 (TWIK-related acid-sensitive K channel 3, KCNK9, K2P9.1) two pore domain potassium (K) channels are genetically imprinted and underlie leak K currents in a number of mammalian neurons. A single point mutation in human TASK3 channels (G236R) has been shown to be responsible for a maternally transmitted developmental disorder, Birk Barel mental retardation dysmorphism syndrome (Barel et al., 2008). The same mutation in mouse TASK3 channels leads to migration defects in developing mouse cortical pyramidal neurons (Bando et al., 2014). We have shown that this mutation results in functional TASK3 channel currents which have a substantially reduced amplitude and which display inward rectification (Veale et al., 2014). The aim of this study is to determine whether the charge of the amino acid substitution at this position is important for changes in current amplitude and current inward rectification and whether mutated human and mouse homologues of TASK3 have similar properties.tsA-201 cells were transiently transfected with wild type and mutated human and mouse TASK3 channels. The whole cell patch clamp technique was used to obtain current recordings. Wild-type human TASK3 current density, measured as the difference current density between that at -40 mV and that at -80 mV (Veale et al., 2014) had an amplitude of 66 ± 4 pA/pF (mean ± S.E.M., n = 45) and was outwardly rectifying in normal physiological solutions. Mutation to a positive lysine residue (G236K) gave substantially smaller current densities (19 ± 2 pA/pF, n = 4) which showed inward rectification. In contrast, mutation to a negative glutamate residue (G236E) gave current densities similar to wild type (80 ± 3 pA/pF, n = 5) which showed no inward rectification. Mutations in mouse TASK3 channels showed the same profile as those in human TASK3 channels.It is concluded that the nature of the amino acid at position G236, in transmembrane domain 4 at the cytoplasmic end of the inner vestibule of both human and mouse TASK3 channels, determines both the amplitude of current through the channel and whether current shows inward rectification.