Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and G(s), G(i), and G(q) protein-coupled receptors

Mechano-sensitive and fatty acid-activated K+ belong to the structural clas s of K+ channel with two pore domains. Here, we report the isolation and th e characterization of a novel member of this family. This channel, called T REK2, is closely related to TREK1 (78% of homology), Its gene is located on chromosome 14q31. TREK2 is abundantly expressed in pancreas and kidney and to a lower level in brain, testis, colon, and small intestine. In the cent ral nervous system, TREK2 has a widespread distribution with the highest le vels of expression in cerebellum, occipital lobe, putamen, and thalamus. In transfected cells, TREK2 produces rapidly activating and non-inactivating outward rectifier K+ currents. The single-channel conductance is 100 picosi emens at +40 mV in 150 mM K+, The currents can be strongly stimulated by po lyunsaturated fatty acid such as arachidonic, docosahexaenoic, and linoleic acids and by lysophosphatidylcholine, The channel is also activated by aci dification of the intracellular medium. TREK2 is blocked by application of intracellular cAMP. As with TREK1, TREK2 is activated by the volatile gener al anesthetics chloroform, halothane, and isoflurane and by the neuroprotec tive agent riluzole. TREK2 can be positively or negatively regulated by a v ariety of neurotransmitter receptors, Stimulation of the G(s)-coupled recep tor 5HT4sR or the G(q)-coupled receptor mGluR1 inhibits channel activity, w hereas activation of the G(1)-coupled receptor mGluR2 increases TREK2 curre nts. These multiple types of regulations suggest that TREK2 plays an import ant role as a target of neurotransmitter action.