The neuronal background K2P channels: focus on TREK1

Background K+ channels are dimers of K2P channel subunits, each of which is composed of four transmembrane segments and two P domains arranged in tandem.The Aplysia serotonin-sensitive S-type K+ channel and the Lymnaea anaesthetic-sensitive K(An) channels are classical examples of background K+ channels.Background K+ channels and their regulation by membrane-receptor-coupled second messengers, as well as pharmacological agents, influence neuronal resting membrane potential, action potential duration, membrane input resistance and, consequently, neurotransmitter release.K2P channels diverge from the constant-field Goldman–Hodgkin–Katz (GHK) current formulation and are characterized by complex permeation and gating mechanisms.TREK1 can be activated by mechanical stimulation, intracellular acidosis and warm temperature, thus qualifying as a polymodal sensory ion channel integrating multiple physical and chemical stimuli.Besides its activation by physical stimuli, TREK1 is also upmodulated by various chemical stimuli including cellular lipids and volatile general anaesthetics.Recent evidence suggests that both mechanical and lipid activations of TREK1 may be functionally linked. The proposed model states that a tight dynamic interaction of the cytosolic carboxy-terminal domain of TREK1 with the inner leaflet of the plasma membrane is central to the mechanism of channel gating and regulation by membrane receptors/second messenger pathways.TREK1 is downmodulated by the stimulation of both Gs- and Gq-coupled membrane receptors. Recent studies have identified the second messenger pathways involved in this regulation, including phosphorylation pathways and PtdIns(4,5)P2 hydrolysis.The Trek1−/− mutant mice are healthy, fertile and do not display any visible morphological difference. However, recent studies indicate a central role for TREK1 in anaesthesia, neuroprotection, pain perception and depression.Both the Aplysia S-type K+ channel and mammalian TREK1 are involved in controlling the excitability of presynaptic neurons through the pathway mediated by serotonin, cyclic AMP and protein kinase A. However, in the dorsal raphé neurons, serotonin probably opens TREK1 though the Gi/o pathway, whereas serotonin closes the S-type K+ channel through the Gs pathway in molluscan sensory neurons.