TRENDS in Neurosciences Vol.24 No.6 June 2001 http://tins.trends.com 339 Review Review Review Leak or background K + selective channels – defined by a lack of voltage- and time-dependency, and with a linear current to voltage relationship in a symmetrical K + gradient – play an essential role in setting the resting membrane potential, tuning the action potential duration and modulating the responsiveness to synaptic inputs. Regulation of background K + channels by neurotransmitters and second messengers is central for synaptic function 1,2 . The most extensively studied native background K + channel is the S channel in the marine snail Aplysia sensory neurones 1 . Closing of the S-type background K + channel by 5-HT receptor activation is involved in presynaptic sensitization, a simple form of learning 2 . Additionally, neuronal background K + channels are the targets of an important class of pharmacological agents, the volatile general anaesthetics 3–7 . Mammalian K + channel subunits (~80 genes) can be divided into three main structural classes comprising two transmembrane segments (TMS), four-TMS or six-TMS (Ref. 8). The common feature of all K + channels is the presence of a conserved motif called the P domain, which is part of the K + conduction pathway 9 . The two-TMS channels comprise a single P domain and encode the inward rectifiers. These K + channels, which operate at negative membrane potentials, contribute to the setting of the resting membrane potential. The six- TMS channels, including the voltage-gated and the Ca 2+ -activated K + channels, similarly comprise a single P domain. These channels, which are usually activated at depolarized membrane potentials, mostly contribute to the repolarization of the action potential. By contrast, the most recently discovered class of four-TMS subunits is characterized by the http://tins.trends.com 0166-2236/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. 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Patel and Eric Honoré Mammalian 2P domain K + channels are responsible for background or ‘leak’ K + currents.These channels are regulated by various physical and chemical stimuli, including membrane stretch, temperature, acidosis, lipids and inhalational anaesthetics. Furthermore, channel activity is tightly controlled by membrane receptor stimulation and second messenger phosphorylation pathways.Several members of this novel family of K + channels are highly expressed in the central and peripheral nervous systems in which they are proposed to play an important physiological role.The pharmacological modulation of this novel class of ion channels could be of interest for both general anaesthesia and ischaemic neuroprotection. Amanda J. Patel Eric Honoré* Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UMR6097, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France. *e-mail: honore@ ipmc.cnrs.fr