TRESK (TWIK-related spinal cord K + channel) is the most recently identified member of the two-pore-domain potassium channel (K 2P ) family, the molecular source of background potassium currents. Human TRESK channels are not affected by external acidification. However, the mouse orthologue displays moderate pH dependence isolated to a single histidine residue adjacent to the GYG selectivity filter. In the human protein, sequence substitution of tyrosine by histidine at this critical position generated a mutant that displays almost identical proton sensitivity compared with mouse TRESK. In contrast to human TRESK, which is specifically located in spinal cord, we detected mouse TRESK (mTRESK) mRNA in several epithelial and neuronal tissues including lung, liver, kidney, brain and spinal cord. As revealed by endpoint and quantitative RT-PCR, mTRESK channels are mainly expressed in dorsal root ganglia (DRG) and on the transcript level represent the most important background potassium channel in this tissue. DRG neurones of all sizes were labelled by in situ hybridizations with TRESK-specific probes. In DRG neurones of TRESK[G339R] functional knock-out (KO) mice the standing outward current IK so was significantly reduced compared with TRESK wild-type (WT) littermates. Different responses to K 2P channel regulators such as bupivacaine, extracellular protons and quinidine corroborated the finding that approximately 20% of IK so is carried by TRESK channels. Unexpectedly, we found no difference in resting membrane potential between DRG neurones of TRESK[WT] and TRESK[G339R] functional KO mice. However, in current-clamp recordings we observed significant changes in action potential duration and amplitude of after-hyperpolarization. Most strikingly, cellular excitability of DRG neurones from functional KO mice was significantly augmented as revealed by reduced rheobase current to elicit action potentials. Background (leak) potassium currents substantially contribute to the resting membrane potential of several excitable and non-excitable cells. This K + conductance plays an important role in setting the cellular excitability and regulates the firing rate of neurones. Two-poredomain potassium (K 2P ) channels, when expressed in heterologous systems, show constitutive activity throughout the physiological range of membrane potential and thus are classified as background K + channels. Functional K 2P channels consist of two subunits, each of which has two pore domains and four transmembrane segments. In mammals 15 different K 2P channel subunits (KCNK) have been identified and, due to structural and functional characteristics, they are divided into several subfamilies, e.g. acid-sensitive TASK channels and lipid-sensitive mechano-gated TREK/TRAAK channels (reviewed by Goldstein et al. 2001;Bayliss et al. 2003; Honoré, 2007). The activity of K 2P channels is regulated by various physical and chemical stimuli such as temperature , membrane stress (Maingret et al. 1999), protons (Duprat et al. 1997Rajan et al. 2000), free fat...