THIK-1 and THIK-2, a Novel Subfamily of Tandem Pore Domain K+ Channels

Two cDNAs encoding novel K+channels, THIK-1 and THIK-2 (tandem pore domainhalothane inhibited K+channel), were isolated from rat brain. The proteins of 405 and 430 amino acids were 58% identical to each other. Homology analysis showed that the novel channels form a separate subfamily among tandem pore domain K+ channels. The genes of the human orthologs were identified as human genomic data base entries. They possess one intron each and were assigned to chromosomal region 14q24.1–14q24.3 (human (h) THIK-1) and 2p22–2p21 (hTHIK-2). In rat (r), THIK-1 (rTHIK-1) is expressed ubiquitously; rTHIK-2 expression was found in several tissues including brain and kidney. In situ hybridization of brain slices showed that rTHIK-2 is strongly expressed in most brain regions, whereas rTHIK-1 expression is more restricted. Heterologous expression of rTHIK-1 in Xenopus oocytes revealed a K+channel displaying weak inward rectification in symmetrical K+ solution. The current was enhanced by arachidonic acid and inhibited by halothane. rTHIK-2 did not functionally express. Confocal microscopy of oocytes injected with green fluorescent protein-tagged rTHIK-1 or rTHIK-2 showed that both channel subunits are targeted to the outer membrane. However, coinjection of rTHIK-2 did not affect the currents induced by rTHIK-1, indicating that the two channel subunits do not form heteromers.AF287301AF287302AF287303 Two cDNAs encoding novel K+channels, THIK-1 and THIK-2 (tandem pore domainhalothane inhibited K+channel), were isolated from rat brain. The proteins of 405 and 430 amino acids were 58% identical to each other. Homology analysis showed that the novel channels form a separate subfamily among tandem pore domain K+ channels. The genes of the human orthologs were identified as human genomic data base entries. They possess one intron each and were assigned to chromosomal region 14q24.1–14q24.3 (human (h) THIK-1) and 2p22–2p21 (hTHIK-2). In rat (r), THIK-1 (rTHIK-1) is expressed ubiquitously; rTHIK-2 expression was found in several tissues including brain and kidney. In situ hybridization of brain slices showed that rTHIK-2 is strongly expressed in most brain regions, whereas rTHIK-1 expression is more restricted. Heterologous expression of rTHIK-1 in Xenopus oocytes revealed a K+channel displaying weak inward rectification in symmetrical K+ solution. The current was enhanced by arachidonic acid and inhibited by halothane. rTHIK-2 did not functionally express. Confocal microscopy of oocytes injected with green fluorescent protein-tagged rTHIK-1 or rTHIK-2 showed that both channel subunits are targeted to the outer membrane. However, coinjection of rTHIK-2 did not affect the currents induced by rTHIK-1, indicating that the two channel subunits do not form heteromers.AF287301AF287302AF287303 tandem pore domain potassium channels tandem pore domain halothane-inhibited K+ channel rat THIK human THIK expressed sequence tag polymerase chain reaction genomic survey sequence enhanced green fluorescent protein base pair(s) The family of tandem pore domain potassium (2P K+)1 channels can be divided into several subfamilies: (i) the acid-sensitive 2P K+ channels TASK-1 to -3 (1Duprat F. Lesage F. Fink M. Reyes R. Heurteaux C. Lazdunski M. EMBO J. 1997; 16: 5464-5471Crossref PubMed Scopus (549) Google Scholar, 2Kim D. Fujita A. Horio Y. Kurachi Y. Circ. Res. 1997; 82: 513-518Crossref Scopus (114) Google Scholar, 3Leonoudakis D. Gray A.T. Winegar B.D. Kindler C.H. Harada M. Taylor D.M. Chavez R.A. Forsayeth J.R. Yost C.S. J. Neurosci. 1998; 18: 868-877Crossref PubMed Google Scholar, 4Reyes R. Duprat F. Lesage F. Fink M. Salinas M. Farman N. Lazdunski M. J. Biol. Chem. 1998; 273: 30863-30869Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar, 5Rajan S. Wischmeyer E. Liu G.X. Preisig-Müller R. Daut J. Karschin A. Derst C. J. Biol. Chem. 2000; 275: 16650-16657Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 6Kim Y. Bang H. Kim D. J. Biol. Chem. 2000; 275: 9340-9347Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar), (ii) the mechanosensitive 2P K+ channels TREK-1/-2 and TRAAK (7Fink M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (425) Google Scholar, 8Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (398) Google Scholar, 9Meadows H.J. Benham C.D. Cairns W. Gloger I. Jennings C. Medhurst A.D. Murdock P. Chapman C.G. Pfluegers Arch. 2000; 439: 714-722Crossref PubMed Scopus (0) Google Scholar, 10Bang H. Kim Y. Kim D. J. Biol. Chem. 2000; 275: 17412-17419Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 11Lesage F. Terrenoire C. Romey G. Lazdunski M. J. Biol. Chem. 2000; 275: 28398-28405Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar) and (iii) the weakly inwardly rectifying 2P K+ channels TWIK-1/-2, and the structurally related but nonfunctional KCNK7 (12Lesage F. Guillemare E. Fink M. Duprat F. Lazdunski M. Romey G. Barhanin J. EMBO J. 1996; 15: 1004-1011Crossref PubMed Scopus (460) Google Scholar, 13Chavez R.A. Gray A.T. Zhao B.B. Kindler C.H. Mazurek M.J. Mehta Y. Forsayeth J.R. Yost C.S. J. Biol. Chem. 1999; 274: 7887-7892Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 14Salinas M. Reyes R. Lesage F. Fosset M. Heurteaux C. Romey G. Lazdunski M. J. Biol. Chem. 1999; 274: 11751-11760Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 15Patel A.J. Maingret F. Magnone V. Fosset M. Lazdunski M. Honoré E. J. Biol. Chem. 2000; 275: 28722-28730Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). All 2P K+ channels have four transmembrane regions (M1-M4) and two typical pore-forming regions (P1 and P2) including the K+ selectivity filter consensus sequence TxGYFG (12Lesage F. Guillemare E. Fink M. Duprat F. Lazdunski M. Romey G. Barhanin J. EMBO J. 1996; 15: 1004-1011Crossref PubMed Scopus (460) Google Scholar) and a large extracellular loop between M1 and P1. The extracellular loop is thought to participate in dimerization of subunits, which in some 2P K+ channels may involve disulfide bond formation (16Lesage F. Reyes R. Fink M. Duprat F. Guillemare E. Lazdunski M. EMBO J. 1996; 15: 6400-6407Crossref PubMed Scopus (154) Google Scholar). The N terminus of the 2P K+channels is usually very short, whereas the C-terminal domain is much larger and determines many functional properties. Relatively little is known about the function of 2P K+channels in vivo. Recently, endogenous currents with properties similar to those of TASK channels have been found in the heart (17Kim Y. Bang H. Kim D. Am. J. Physiol. 1999; 277: H1669-H1678PubMed Google Scholar), in arterial chemoreceptor cells (18Buckler K.J. Williams B.A. Honoré E. J. Physiol. ( Lond. ). 2000; 525: 135-142Crossref PubMed Scopus (369) Google Scholar), in zona glomerulosa cells of the adrenal cortex (19Czirják G. Fischer T. Spät A. Lesage F. Enyedi P. Mol. Endocrinol. 2000; 14: 863-874PubMed Google Scholar), in cerebellar granular cells (20Millar J.A. Barratt L. Southan A.P. Page K.M. Fyffe R.E.W. Robertson B. Mathie A. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3614-3618Crossref PubMed Scopus (240) Google Scholar), and in motoneurons (21Talley E.M. Lei Q. Sirois J.E. Bayliss D.A. Neuron. 2000; 25: 399-410Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar). TASK-1 currents have been shown to be coupled to the activation of thyrotropin-releasing hormone receptor 1 (TRH-R1; Ref. 21Talley E.M. Lei Q. Sirois J.E. Bayliss D.A. Neuron. 2000; 25: 399-410Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar) and angiotensin II receptors (AT1a; Ref.19Czirják G. Fischer T. Spät A. Lesage F. Enyedi P. Mol. Endocrinol. 2000; 14: 863-874PubMed Google Scholar); thus, TASK-1 channels are regulated also by mechanisms other than extracellular pH. Furthermore, another member of this subfamily, TASK-3, is activated by depolarization and modulated by extracellular divalent cations (5Rajan S. Wischmeyer E. Liu G.X. Preisig-Müller R. Daut J. Karschin A. Derst C. J. Biol. Chem. 2000; 275: 16650-16657Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). With TREK-1, TREK-2, and TRAAK, three mechanosensitive channels have been cloned (10Bang H. Kim Y. Kim D. J. Biol. Chem. 2000; 275: 17412-17419Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 22Maingret F. Fosset M. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 1999; 274: 1381-1387Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar). Other factors that have been reported to modulate the activity of these mechanosensitive channels include heat (TREK-1; Ref. 23Maingret F. Lauritzen I. Patel A.J. Heurteaux C. Reyes R. Lesage F. Lazdunski M. Honoré E. EMBO J. 2000; 19: 2483-2491Crossref PubMed Scopus (417) Google Scholar), lysophospholipids (TREK-1, TRAAK; Ref. 24Maingret F. Patel A.J. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 2000; 275: 10128-10133Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar), arachidonic acid (TRAAK; Ref. 7Fink M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (425) Google Scholar), and intracellular pH (TREK-1; Ref. 25Maingret F. Patel A.J. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 1999; 274: 26691-26696Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). The third subfamily of 2P K+ channels so far comprises TWIK-1 and TWIK-2, both of which are expressed in multiple tissues (12Lesage F. Guillemare E. Fink M. Duprat F. Lazdunski M. Romey G. Barhanin J. EMBO J. 1996; 15: 1004-1011Crossref PubMed Scopus (460) Google Scholar, 13Chavez R.A. Gray A.T. Zhao B.B. Kindler C.H. Mazurek M.J. Mehta Y. Forsayeth J.R. Yost C.S. J. Biol. Chem. 1999; 274: 7887-7892Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar,15Patel A.J. Maingret F. Magnone V. Fosset M. Lazdunski M. Honoré E. J. Biol. Chem. 2000; 275: 28722-28730Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). TWIK-1 shows weak inward rectification with symmetrical K+ concentrations (12Lesage F. Guillemare E. Fink M. Duprat F. Lazdunski M. Romey G. Barhanin J. EMBO J. 1996; 15: 1004-1011Crossref PubMed Scopus (460) Google Scholar). 2E. Wischmeyer and A. Karschin, unpublished information. The current carried by TWIK-2 is heat-sensitive and shows rapid time-dependent inactivation at 37 °C (15Patel A.J. Maingret F. Magnone V. Fosset M. Lazdunski M. Honoré E. J. Biol. Chem. 2000; 275: 28722-28730Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). Both channels may contribute to setting the resting membrane potential, but their specific function in various tissues is not yet clear. In this paper we describe the cloning of the first two members of a novel subfamily of 2P K+ channels. One of these channels, rTHIK-1, was found to be expressed in all tissues tested. Heterologous expression of rTHIK-1 in Xenopus oocytes induced a current that could be activated by arachidonic acid and inhibited by the volatile anesthetic halothane. The second novel 2P K+channel, THIK-2, is closely related to THIK-1 (58% identity at the amino acid level) but could not be functionally expressed. THIK-2 was strongly expressed in several tissues including stomach, liver, and kidney and was particularly abundant in the brain. BLAST searches of the expressed sequence tag data base (dbEST), the genomic survey sequence data base (dbGSS), and the human genomic data base (htgs) identified several human and rat EST clones, one human GSS clone, and three human genomic data base entries of novel 2P K+ channel subunits. One rat EST clone (GenBankTM accession number AI070460) and one human GSS clone (GenBankTM accession number AQ898820) were purchased from Research Genetics (Huntsville, AL) and completely sequenced. About 1 × 106 clones of a λ-ZAPII rat brain or a λ-ZAPII rat heart cDNA library (Stratagene) plated with XL1-Blue MRF′ cells were screened with Digoxigenin-labeled THIK-2 andTHIK-1 fragments derived from the EST or GSS clones, respectively, and positive clones were detected using CSPD (Roche Molecular Biochemicals) as chemoluminescence substrate. After purification of isolated plaques by two further screenings, pBSK+ plasmids containing the cDNAs were excised from λ-clones and sequenced. For sequence analysis, the GCG at the was The was of sequence consensus the sequence the of multiple and the of the were the from rat tissues was using the and with II with a or a was with polymerase were as at at and 1 at °C each activation at °C and at fragments were a were by analysis of using of clone from the human G. C. H. N. D. D. C. C. J. J. Mol. 1996; PubMed Scopus Google Scholar). The were were as at at 1 at each two of the with data in the the were to cDNAs encoding rTHIK-1, and between the two were cloned into the expression of M. expression were and injected or in into oocytes at were at °C in 1 1 pH with and and were with a which a of a were at to using The were in a and with or K+ 1 1 pH were and their were and was at °C were a and After in in were in and in were from the with to other known to a of and were as (i) and (ii) (i) and (ii) were with or by (Roche Molecular Biochemicals) and hybridization at concentrations of × of hybridization were and at °C in of containing and the After were × in and 1 in at and in at were and to For were in and in For and of brain with and were with were with at 37 °C hybridization or with a containing a of in a of specific hybridization Two cDNA novel 2P K+ channels were isolated from two rat cDNA The first channel was isolated from a rat brain and a rat heart library and was THIK-1 tandem pore domain K+ The closely related channel was found in the rat brain library and was THIK-2 the that was not functional expressed in Xenopus analysis of the isolated cDNA clones revealed rTHIK-1 and rTHIK-2 The proteins of 405 (rTHIK-1) and 430 amino respectively, which the typical of 2P K+ four transmembrane regions, two pore-forming regions, a large extracellular between M1 and a N terminus and a larger in and several intracellular protein protein and were found in both In the rTHIK-1 two whereas rTHIK-1 The rTHIK-2 protein is at the N including three protein and several amino acid and amino acid sequence of rTHIK-1 and rTHIK-2 regions are shown in and pore regions are In protein and are the amino acid were identified using the identified the human orthologs of THIK-2 in data base and of THIK-1 in two data base entries In with the human the two novel channel genes were and The human channel subunits are and identical to their rat and are identical and similar to each whereas about identity was found to other 2P K+ channels the intracellular was amino acids than that of other cloned 2P K+ channels. The C-terminal of the THIK channels are identical to each other whereas was found to other C-terminal of 2P K+ The pore regions of both THIK channels are identical in a of amino acids in the first pore region and one in the second whereas is to other 2P K+ channels the the of THIK channels and the is that THIK 1 and THIK-2 form a novel subfamily among the 2P K+ channels. sequence the C-terminal and of THIK-1 and THIK-2 C-terminal is in the of the entries of the human showed that both genes have a similar with a large intron of and respectively, the region at the first pore intron is in all 2P K+ channel genes cloned so assigned to the human chromosomal region 2p22–2p21 between and was assigned to chromosomal region 14q24.1–14q24.3 between and which is very to the human The of the chromosomal are in I. The of the rTHIK-1 and rTHIK-2 was by were to positive to genomic were from all tissues tested. In rTHIK-2 expression was found in liver, stomach, and but not in and The of rTHIK-1 and rTHIK-2 in the rat brain as detected by in situ hybridization is with little in Two were The were identical each indicating that the were rTHIK-2 was found to be expressed in most brain regions, with in the cerebellar the and of the and in the and of the were also found in the the the the and some of the In the were found in all in the and and in the rTHIK-2 was also found in some cells as the of the rTHIK-2 was found to be from the and from most of the and as as all of rTHIK-1 and rTHIK-2 in the rat is is is is is is situ hybridization rat brain were to the very that brain regions with expression or expression are in the of and is in a In situ hybridization rat brain were to the very that brain regions with expression or expression are in the of and In rTHIK-1 expression was found to be weak and to a brain regions and expression were detected in the of the in the the and in and and Other were The was positive in the was in the and the of the particularly in the a specific were the of the the of the a of the and one and the of the of rTHIK-1 into Xenopus large currents were using the which were not The of the currents at was in the of activation in to was not to a showed activation of at a currents did not The of rTHIK-1 showed weak With rectification was whereas with symmetrical weak inward rectification was found K+ was to the selectivity of rTHIK-1, the were very to the K+ the of intracellular K+ of The to the data a of as be K+ channels. THIK-1 could be by of 1 the current at the of by about not In the currents in Xenopus oocytes of rTHIK-2 were not from those of or oocytes both channel proteins were and targeted to the rTHIK-1 and rTHIK-2 were with at the N of microscopy showed membrane that was very similar to that found of rTHIK-2 subunits to be targeted to the outer membrane. The the of functional expression of rTHIK-2 was further by subunits in which the first of the region was to the second of rTHIK-1 and of the did not current in Xenopus or inwardly rectifying K+channel subunits that do not functionally as can the activity of other subunits by we the that rTHIK-1 and rTHIK-2 subunits to form channels. rTHIK-1 and rTHIK-2 were injected at all current properties were from rTHIK-1 and current were not and Furthermore, the currents induced by of rTHIK-1 were by of larger of rTHIK-2 The of of rTHIK-2 and rTHIK-1 subunits that rTHIK-2 is not a of the rTHIK-1 functional to other members of the two pore domain K+channel we the of rTHIK-1 channel activity by various as extracellular of the acid arachidonic or of the volatile anesthetic The current carried by rTHIK-1 was weakly inhibited by extracellular to pH which is in to the pH of TASK-1 at pH as in B. the pH to inhibited the current carried by rTHIK-1 by to TASK-3, of rTHIK-1 with a and was of the membrane The of rTHIK-1 to intracellular pH was by the was and which the intracellular pH by about 1 in the current carried by rTHIK-1 indicating that rTHIK-1 is not modulated by intracellular pH. been reported to be heat-sensitive F. Lauritzen I. Patel A.J. Heurteaux C. Reyes R. Lesage F. Lazdunski M. Honoré E. EMBO J. 2000; 19: 2483-2491Crossref PubMed Scopus (417) Google Scholar), we also the of the from to 37 °C the current by a of in with whereas is by a of the F. Lauritzen I. Patel A.J. Heurteaux C. Reyes R. Lesage F. Lazdunski M. Honoré E. EMBO J. 2000; 19: 2483-2491Crossref PubMed Scopus (417) Google Scholar). TREK-1, rTHIK-1 is not a heat-sensitive also been shown to and TRAAK F. Patel A.J. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 2000; 275: 10128-10133Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar). of to rTHIK-1 induced a very to in current which may be to a of the of arachidonic acid to the induced a rapid in the current carried by rTHIK-1 channels could be In the of arachidonic the current was by at can be from the current activated by arachidonic acid was at the potassium the K+ was The of the of arachidonic acid rTHIK-1 could be by a of and a of The of arachidonic acid reported are similar to the found in and TRAAK (7Fink M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (425) Google Scholar, 9Meadows H.J. Benham C.D. Cairns W. Gloger I. Jennings C. Medhurst A.D. Murdock P. Chapman C.G. Pfluegers Arch. 2000; 439: 714-722Crossref PubMed Scopus (0) Google Scholar, 24Maingret F. Patel A.J. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 2000; 275: 10128-10133Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar). Two of the known 2P K+ channels, and are activated by the volatile anesthetic A.J. Honoré E. Lesage F. Fink M. Romey G. Lazdunski M. Neurosci. 1999; PubMed Scopus Google Scholar). in Xenopus oocytes showed that the current carried by rTHIK-1 was and inhibited by and the membrane was at of rTHIK-1 currents by The of the a of and a of the of data not THIK-1 and THIK-2 are the first two members of a novel 2P K+ channel the typical of other 2P K+ channels, as four transmembrane regions, two pore-forming regions, and a large extracellular the two novel channels are about identical to the other known 2P K+ channels but identical to each other. One is the larger containing three or one (rTHIK-1) In the THIK-2 protein N terminus containing several of and The C-terminal domain of THIK-1 and THIK-2 shows to other 2P K+ channels. The of the current induced by of rTHIK-1 in Xenopus oocytes the K+ K+ was that the THIK channels are to K+ The current induced by expression of rTHIK-1 rectification at K+ and weak inward rectification with symmetrical K+ could be activated by arachidonic acid and inhibited by of 2P K+ TWIK-2, which is in the been found to be inhibited by both and (15Patel A.J. Maingret F. Magnone V. Fosset M. Lazdunski M. Honoré E. J. Biol. Chem. 2000; 275: 28722-28730Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). In both and TASK-1 are activated by and and is activated by and A.J. Honoré E. Lesage F. Fink M. Romey G. Lazdunski M. Neurosci. 1999; PubMed Scopus Google Scholar). TREK-1, and THIK-1 are all expressed in specific regions of the brain. The reported that the of volatile the brain may be more than are of the that the the of THIK-1 is than the the anesthetic in PubMed Scopus Google Scholar). we to the K+ channels this from some of the other 2P of rTHIK-2 in Xenopus oocytes did not The of functional expression of rTHIK-2 was not to microscopy showed rTHIK-2 channels in the outer membrane in rTHIK-2 that expression of functional channels, we and However, of the two was the the nonfunctional of rTHIK-2 in Xenopus oocytes is that rTHIK-2 be a of rTHIK-1 by with is currents by of rTHIK-1 were by coinjection of larger rTHIK-2 In situ hybridization in the brain showed little between rTHIK-1 and which also In the expression of rTHIK-2 in and and the specific expression in several the that rTHIK-2 is functionally in but the that rTHIK-2 or specific intracellular to form a The expression in and that rTHIK-2 may also a in Both human THIK genes have one very large in the THIK-1 and in the THIK-2 that the region of the first pore In this the THIK genes are similar to the The genes of the and the possess several in the region (10Bang H. Kim Y. Kim D. J. Biol. Chem. 2000; 275: 17412-17419Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, F. Maingret F. Lazdunski M. 2000; PubMed Scopus Google Scholar, I. Lesage F. Barhanin J. 1998; PubMed Scopus Google Scholar), but intron the of the first pore region is in all 2P K+channel genes cloned so far in in most of the 2P K+ channels of A. A. L. N. Y. Acad. Sci. 1999; PubMed Scopus Google Scholar) is the of 2P K+ channel genes at the chromosomal have shown that THIK-1 to the region the of as The other 2P K+ channel known so far are TRAAK and KCNK7 F. Maingret F. Lazdunski M. 2000; PubMed Scopus Google Scholar) and TWIK-1 and F. Lazdunski M. 1998; PubMed Scopus Google Scholar). data are with a all 2P K+channels that was to several in 2P K+ channels can be in subfamilies: and channels a of and that are usually not to one of the The current in the at symmetrical K+ concentrations was found to be inwardly rectifying TWIK-2, and rectifying (TREK-1, or (TREK-1, of the 2P K+ channels a to intracellular or extracellular pH The of the 2P K+channels is also very and not related to 2P K+ channels are activated by volatile (TREK-1, other channels are inhibited channels are activated by acids as arachidonic acid (TREK-1, TRAAK, TWIK-2, THIK-1) or by as and In some of the 2P K+ channels are mechanosensitive (TREK-1, TREK-2, and or heat-sensitive The most of all 2P K+ channels known so far is that their by and is very The in their function is related to this which to be in the cells in which the channels are expressed. and and with