Pharmacology of neuronal background potassium channels

Background or leak conductances are a major determinant of membrane resting potential and input resistance, two key components of neuronal excitability. The primary structure of the background K(+) channels has been elucidated. They form a family of channels that are molecularly and functionally divergent from the voltage-gated K(+) channels and inward rectifier K(+) channels. In the nervous system, the main representatives of this family are the TASK and TREK channels. They are relatively insensitive to the broad-spectrum K(+) channel blockers tetraethylammonium (TEA), 4-aminopyridine (4-AP), Cs(+), and Ba(2+). They display very little time- or voltage-dependence. Open at rest, they are involved in the maintenance of the resting membrane potential in somatic motoneurones, brainstem respiratory and chemoreceptor neurones, and cerebellar granule cells. TASK and TREK channels are also the targets of many physiological stimuli, including intracellular and extracellular pH and temperature variations, hypoxia, bioactive lipids, and neurotransmitter modulation. Integration of these different signals has major effects on neuronal excitability. Activation of some of these channels by volatile anaesthetics and by other neuroprotective agents, such as riluzole and unsaturated fatty acids, illustrates how the neuronal background K(+) conductances are attractive targets for the development of new drugs.