Mechano- or Acid Stimulation, Two Interactive Modes of Activation of the TREK-1 Potassium Channel

TREK-1 is a member of the novel structural class of K+ channels with four transmembrane segments and two pore domains in tandem (1Fink M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (421) Google Scholar, 2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar). TREK-1 is opened by membrane stretch and arachidonic acid. It is also an important target for volatile anesthetics (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar, 3Patel A.J. Honoré E. Lesage F. Fink M. Romey G. Lazdunski M. Nature Neurosci. 1999; 2: 422-426Crossref PubMed Scopus (564) Google Scholar). Here we show that internal acidification opens TREK-1. Indeed, lowering pHi shifts the pressure-activation relationship toward positive values and leads to channel opening at atmospheric pressure. The pHi-sensitive region in the carboxyl terminus of TREK-1 is the same that is critically involved in mechano-gating as well as arachidonic acid activation. A convergence, which is dependent on the carboxyl terminus, occurs between mechanical, fatty acids and acidic stimuli. Intracellular acidosis, which occurs during brain and heart ischemia, will induce TREK-1 opening with subsequent K+ efflux and hyperpolarization. TREK-1 is a member of the novel structural class of K+ channels with four transmembrane segments and two pore domains in tandem (1Fink M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (421) Google Scholar, 2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar). TREK-1 is opened by membrane stretch and arachidonic acid. It is also an important target for volatile anesthetics (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar, 3Patel A.J. Honoré E. Lesage F. Fink M. Romey G. Lazdunski M. Nature Neurosci. 1999; 2: 422-426Crossref PubMed Scopus (564) Google Scholar). Here we show that internal acidification opens TREK-1. Indeed, lowering pHi shifts the pressure-activation relationship toward positive values and leads to channel opening at atmospheric pressure. The pHi-sensitive region in the carboxyl terminus of TREK-1 is the same that is critically involved in mechano-gating as well as arachidonic acid activation. A convergence, which is dependent on the carboxyl terminus, occurs between mechanical, fatty acids and acidic stimuli. Intracellular acidosis, which occurs during brain and heart ischemia, will induce TREK-1 opening with subsequent K+ efflux and hyperpolarization. transmembrane segment(s) arachidonic acid 4-morpholineethanesulfonic acid number of channels × open channel probability The near completion of the sequencing of the nematode Caenorhabditis elegans genome recently identified more than 80 K+ channel genes divided into three major structural classes: (i) the inward rectifiers with two TMS1 and a single P domain; (ii) the Shaker types with six TMS and a single P domain comprising the voltage-gated Kvs, the calcium-activated Slo, the calcium-regulated SK, the Eag/Erg, and the KQT channels; and (iii) the two P types with 4TMS being the largest structural class (about 50 genes) (4Bargmann C. Science. 1998; 282: 2028-2033Crossref PubMed Scopus (709) Google Scholar, 5Wei A. Jegla T. Salkoff L. Neuropharmacology. 1996; 35: 805-829Crossref PubMed Scopus (218) Google Scholar, 6Lesage F. Lazdunski M. Kurachi Y. Current Topics in Membranes. 46. Academic Press, San Diego, CA1999: 199-222Google Scholar). Despite an overall similar 4TMS/2P structure, the sequence identity between these channels is very low (less than 30%) (5Wei A. Jegla T. Salkoff L. Neuropharmacology. 1996; 35: 805-829Crossref PubMed Scopus (218) Google Scholar, 6Lesage F. Lazdunski M. Kurachi Y. Current Topics in Membranes. 46. Academic Press, San Diego, CA1999: 199-222Google Scholar). The mammalian family of 4TMS/2P K+ channels comprises TWIK-1, TWIK-2, TASK-1, TASK-2, TREK-1, and TRAAK (1Fink M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (421) Google Scholar, 7Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (393) Google Scholar, 8Lesage F. Guillemare E. Fink M. Duprat F. Lazdunski M. Romey G. Barhanin J. EMBO J. 1996; 15: 1004-1011Crossref PubMed Scopus (449) Google Scholar, 9Duprat F. Lesage F. Fink M. Reyes R. Heurteaux C. Lazdunski M. EMBO J. 1997; 16: 5464-5471Crossref PubMed Scopus (535) Google Scholar, 10Reyes 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 (319) Google Scholar, 11Chavez 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 (125) Google Scholar). TWIK-1 and TWIK-2 are widely distributed and encode K+-selective channels with a characteristic weak inward rectification (8Lesage F. Guillemare E. Fink M. Duprat F. Lazdunski M. Romey G. Barhanin J. EMBO J. 1996; 15: 1004-1011Crossref PubMed Scopus (449) Google Scholar, 11Chavez 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 (125) Google Scholar). TASK-1 is found principally in the pancreas, placenta, lung, brain, and heart (9Duprat F. Lesage F. Fink M. Reyes R. Heurteaux C. Lazdunski M. EMBO J. 1997; 16: 5464-5471Crossref PubMed Scopus (535) Google Scholar, 12Leonoudakis 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, 13Kim D. Fujita A. Horio Y. Kurachi Y. Circ. Res. 1998; 82: 513-518Crossref PubMed Scopus (113) Google Scholar). TASK-1 lacks intrinsic voltage sensitivity and is thus a pure background K+-selective channel. Moreover, TASK-1 is extremely sensitive to variations of extracellular pH in a narrow physiological range, with 90% of the maximum current recorded at pH 7.7 and only 10% at pH 6.7 (9Duprat F. Lesage F. Fink M. Reyes R. Heurteaux C. Lazdunski M. EMBO J. 1997; 16: 5464-5471Crossref PubMed Scopus (535) Google Scholar). TASK-2, another background K+ channel recently isolated from human kidney, shares the external pH sensitivity of TASK-1 (10Reyes 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 (319) Google Scholar). Unlike the other 4TMS/2P channels, TASK-2 is almost absent from the brain and is mainly expressed in the kidney. Murine TREK-1 is widely distributed with a strong expression in the brain and in the heart (1Fink M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (421) Google Scholar). It is activated by membrane stretch, by AA as well as inhalational anesthetics, while it is inhibited by a cAMP-dependent phosphorylation (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar, 3Patel A.J. Honoré E. Lesage F. Fink M. Romey G. Lazdunski M. Nature Neurosci. 1999; 2: 422-426Crossref PubMed Scopus (564) Google Scholar). Interestingly, TREK-1 shares the properties of the Aplysia S-type K+ channel, which is involved in presynaptic facilitation underlying a simple form of learning (14Belardetti F. Siegelbaum S.A. Trends Neurosci. 1988; 11: 232-238Abstract Full Text PDF PubMed Scopus (56) Google Scholar, 15Hawkins R.D. Kandel E.R. Siegelbaum S.A. Annu. Rev. Neurosci. 1993; 16: 625-665Crossref PubMed Scopus (315) Google Scholar). TRAAK, another mouse mechano-gated AA-sensitive 4TMS/2P K+channel, is only expressed in neuronal tissues including brain, spinal cord, and retina and lacks sensitivity to cAMP (7Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (393) Google Scholar, 16Maingret F. Fosset M. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 1999; 274: 1381-1387Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). The mammalian mechano-gated K+ channels that have been previously described in cardiac myocytes, neurons and epithelial kidney cells (17Kim D. J. Gen. Physiol. 1992; 100: 1021-1040Crossref PubMed Scopus (105) Google Scholar, 18Kim D. Clapham D.E. Science. 1989; 244: 1174-1176Crossref PubMed Scopus (267) Google Scholar, 19Kim D. Duff R.A. Circ. Res. 1990; 67: 1040-1046Crossref PubMed Scopus (93) Google Scholar, 20Kim D.H. Sladek C.D. Aguadovelasco C. Mathiasen J.R. J. Physiol. (Lond.). 1995; 484: 643-660Crossref Scopus (86) Google Scholar, 21Edwards K.L. Pickard B.G. Wagner E. Greppin H. Millet B. Cell Surface and Signal Transduction. Springer-Verlag, Heidelberg1987: 41-66Google Scholar, 22Gustin M.C. Ito F. Advances in Comparative and Environmental Physiology. 10. Springer-Verlag, Berlin1992: 19-38Google Scholar, 23Hamill O.P. McBride Jr., D. Pharmacol. Rev. 1996; 48: 231-252PubMed Google Scholar, 24Howard J. Roberts W.M. Hudspeth A.J. Annu. Rev. Biophys. Biophys. Chem. 1988; 17: 99-124Crossref PubMed Scopus (222) Google Scholar, 25Martinac B. Jackson M.B. Thermodynamics of Cell Surface Receptors. CRC Press, Inc., Boca Raton, FL1992: 327-352Google Scholar, 26Morris C.E. J. Membr. Biol. 1990; 113: 93-107Crossref PubMed Scopus (470) Google Scholar, 27Sachs F. Crit. Rev. Biomed. Eng. 1988; 16: 141-169PubMed Google Scholar, 28Sachs F. Soc. Gen. Physiol. Ser. 1997; 52: 209-218PubMed Google Scholar, 29Sackin H. Annu. Rev. Physiol. 1995; 57: 333-353Crossref PubMed Scopus (255) Google Scholar, 30Sukharev S.I. Blount P. Martinac B. Kung C. Annu. Rev. Physiol. 1997; 59: 633-657Crossref PubMed Scopus (256) Google Scholar) share the biophysical and pharmacological properties of TREK-1, including single channel conductance (100 pS at 50 mV in symmetrical K+), flickery kinetics, voltage dependence, mechano-gating, and sensitivity to AA (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar, 16Maingret F. Fosset M. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 1999; 274: 1381-1387Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). In the present report, we demonstrate that the AA-sensitive mechano-gated K+ channel TREK-1 is opened by intracellular acidosis. Mutagenesis experiments identify the carboxyl-terminal region of TREK-1 as critical for the integration of both mechanical and acidic stimuli. The cDNA cloning, mutational strategy, cell culture, transfection, and electrophysiology procedures have been previously described elsewhere (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar, 16Maingret F. Fosset M. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 1999; 274: 1381-1387Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). Briefly, murine TREK-1 and TRAAK cDNAs were cloned into pIRES-CD8 vector (1Fink M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (421) Google Scholar, 7Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (393) Google Scholar). COS cells were transfected with the DEAE dextran procedure. The positive cells were visualized using the anti-CD8 antibody-coated bead method (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar). Mutant TREK-1 Δ46 was deleted at Thr-368, Δ89 at Thr-322, Δ100 at Arg-311, Δ103 at Gly-308, and Δ113 at Val-298. The chimera TRAAK/TREK-1 contained the core of TRAAK (truncated at Gly-255) and the carboxyl terminus of TREK-1 (Gly-293 to Thr-368). For whole cell experiments, bath solution (EXT) contained 150 mm NaCl, 5 mm KCl, 3 mmMgCl2, 1 mm CaCl2, 10 mm Hepes, pH 7.4, with NaOH, and pipette solution (INT) contained 150 mm KCl, 3 mm MgCl2, 5 mm EGTA, and 10 mm Hepes, pH 7.2, with KOH. The EXT K+-rich solution contained 150 mm KCl instead of 150 mm NaCl. The HCO3− solution used to induce intracellular acidosis (31Fakler B. Schultz J.H. Yang J. EMBO J. 1996; 15: PubMed Scopus Google Scholar) was by with mm A K+-rich HCO3− solution was by mm KCl with mm For experiments, the EXT solution contained 150 KCl instead of 150 NaCl, and the pipette contained the EXT solution induce intracellular acidosis, mm was for KCl (31Fakler B. Schultz J.H. Yang J. EMBO J. 1996; 15: PubMed Scopus Google Scholar). solution was by pure in an EXT KCl solution mm HCO3− instead of 10 mm for 10 The EXT solution contained mm for mm For experiments, the pipette solution was and the bath solution was For acidic was with and for was with at both acidic and pH similar was an open and at the of the pipette the by a a F. Fosset M. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 1999; 274: 1381-1387Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). were with AA was in at a of with and at for 1 were from TREK-1 cDNA was transfected in COS and channel was recorded using the whole cell In a cell at AA a strong current In the same of which intracellular acidification (31Fakler B. Schultz J.H. Yang J. EMBO J. 1996; 15: PubMed Scopus Google Scholar, C. P. A. Lazdunski M. J. 1988; PubMed Scopus (280) Google AA at AA and HCO3− are on cells Moreover, of mm by an of the of TREK-1 by The of the current by HCO3− a rectification in physiological K+ and at the of mV 1 external is with the shifts to and the 1 AA TRAAK, while HCO3− is 1 The of TREK-1 by the of HCO3− is also at the single channel in the In the pH of the external solution channels is by the pipette and channel is to to intracellular In the of the mechano-gated channel TREK-1 is recorded both at atmospheric and during the of a mm atmospheric channel is very low the and the are by the HCO3− of a which also a strong intracellular acidification C. P. A. Lazdunski M. J. 1988; PubMed Scopus (280) Google leads to TREK-1 opening in the both and are The current by is and at mV to is the which on the membrane for than for C. P. A. Lazdunski M. J. 1988; PubMed Scopus (280) Google Scholar). The of intracellular TREK-1 channel while of intracellular TREK-1 channel The current activated by a strong rectification The of intracellular acidification were also on TREK-1 was recorded at both atmospheric and during membrane intracellular acidification from to channel opening at atmospheric A and is while the single channel conductance is by internal acidosis 3 is at pHi and a of pHi a in channel A mm stretch a channel opening at intracellular pH between and it to open TREK-1 at pHi 3 The relationship of TREK-1 is in physiological intracellular pH 7.2, the relationship is described by a with a for of mm lowering in pHi shifts the toward positive to channel atmospheric at pHi and is at pH 3 The of channel by intracellular acidification was on deleted TREK-1 in the used a including two acidic to pHi and at both atmospheric and during a mm stretch internal pH from to TREK-1 opening at atmospheric and channel during stretch internal pH to opens TREK-1 at atmospheric with at mm of the region of TREK-1 pHi sensitivity mechano-gating of the terminus TREK-1 by pHi TREK-1 at atmospheric Δ46 is opened at pH and while the lacks at pH and is only opened at pH and of Δ89 by a membrane stretch of mm is at both pH and pH and Δ100 is only activated at atmospheric by pH and channel by a mm stretch is only at pH Δ103 is opened at atmospheric by internal acidification at pH pH and of the is only at pH and channel is with Δ113 at both and at pH of the region of TREK-1 shifts the toward more to sensitive channels For the relationship for Δ103 is mm more with that of TREK-1 at pH and 5 pHi to and shifts the relationship toward more positive values and channel by and 5 Unlike TREK-1, TRAAK, the other and AA-sensitive member of the 4TMS/2P K+ channel family at pH is to intracellular acidosis 1 A and the pHi sensitivity of TREK-1 to TRAAK the are and for TREK-1, internal acidosis shifts the toward positive in the opening of the TRAAK/TREK-1 chimera at atmospheric at pH 7.2, and Moreover, HCO3− a strong of the whole cell membrane current of the TRAAK/TREK-1 chimera it on TRAAK 1 mechano-gated K+ channels have been previously described in and cardiac myocytes, in neurons from and of the brain as well as in kidney (17Kim D. J. Gen. Physiol. 1992; 100: 1021-1040Crossref PubMed Scopus (105) Google Scholar, 18Kim D. Clapham D.E. Science. 1989; 244: 1174-1176Crossref PubMed Scopus (267) Google Scholar, 19Kim D. Duff R.A. Circ. Res. 1990; 67: 1040-1046Crossref PubMed Scopus (93) Google Scholar, 20Kim D.H. Sladek C.D. Aguadovelasco C. Mathiasen J.R. J. Physiol. (Lond.). 1995; 484: 643-660Crossref Scopus (86) Google Scholar, 29Sackin H. Annu. Rev. Physiol. 1995; 57: 333-353Crossref PubMed Scopus (255) Google Scholar). to K+ channels (17Kim D. J. Gen. Physiol. 1992; 100: 1021-1040Crossref PubMed Scopus (105) Google Scholar, 18Kim D. Clapham D.E. Science. 1989; 244: 1174-1176Crossref PubMed Scopus (267) Google Scholar, 19Kim D. Duff R.A. Circ. Res. 1990; 67: 1040-1046Crossref PubMed Scopus (93) Google Scholar, 20Kim D.H. Sladek C.D. Aguadovelasco C. Mathiasen J.R. J. Physiol. (Lond.). 1995; 484: 643-660Crossref Scopus (86) Google Scholar). The to induce is between and mm at are and single channel are and at mV in symmetrical K+ for cardiac and brain by stretch are and The probability of these channels to open at a is with a opening at cardiac and neuronal channels are opened by AA and other in the (17Kim D. J. Gen. Physiol. 1992; 100: 1021-1040Crossref PubMed Scopus (105) Google Scholar, 18Kim D. Clapham D.E. Science. 1989; 244: 1174-1176Crossref PubMed Scopus (267) Google Scholar, 19Kim D. Duff R.A. Circ. Res. 1990; 67: 1040-1046Crossref PubMed Scopus (93) Google Scholar, 20Kim D.H. Sladek C.D. Aguadovelasco C. Mathiasen J.R. J. Physiol. (Lond.). 1995; 484: 643-660Crossref Scopus (86) Google Scholar). AA is found in cells with and that AA these fatty acids and fatty acids also these A very important of these mechano-gated K+ channels is that are also by lowering pH the (17Kim D. J. Gen. Physiol. 1992; 100: 1021-1040Crossref PubMed Scopus (105) Google Scholar, 20Kim D.H. Sladek C.D. Aguadovelasco C. Mathiasen J.R. J. Physiol. (Lond.). 1995; 484: 643-660Crossref Scopus (86) Google and the channels are more sensitive to at acidic intracellular recently cloned 4TMS/2P channels, TREK-1 and TRAAK (1Fink M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (421) Google Scholar, 2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar, 7Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (393) Google Scholar, 16Maingret F. Fosset M. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 1999; 274: 1381-1387Abstract Full Text Full Text PDF PubMed Scopus (280) Google have of the properties of mechano-gated channels are activated by cell and membrane stretch (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar, 16Maingret F. Fosset M. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 1999; 274: 1381-1387Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). Moreover, TREK-1 and TRAAK are opened by and acids are to fatty acids (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar, 7Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (393) Google Scholar). The single channel conductance of pS at mV in symmetrical the the and flickery and the voltage are to described channels (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google F. Fosset M. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 1999; 274: 1381-1387Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar, D. J. Gen. Physiol. 1992; 100: 1021-1040Crossref PubMed Scopus (105) Google Scholar, 18Kim D. Clapham D.E. Science. 1989; 244: 1174-1176Crossref PubMed Scopus (267) Google Scholar, 19Kim D. Duff R.A. Circ. Res. 1990; 67: 1040-1046Crossref PubMed Scopus (93) Google Scholar, 20Kim D.H. Sladek C.D. Aguadovelasco C. Mathiasen J.R. J. Physiol. (Lond.). 1995; 484: 643-660Crossref Scopus (86) Google Scholar). The mechano-gated K+ channel TREK-1 is cardiac and neuronal K+ channels (17Kim D. J. Gen. Physiol. 1992; 100: 1021-1040Crossref PubMed Scopus (105) Google Scholar, 18Kim D. Clapham D.E. Science. 1989; 244: 1174-1176Crossref PubMed Scopus (267) Google Scholar, 19Kim D. Duff R.A. Circ. Res. 1990; 67: 1040-1046Crossref PubMed Scopus (93) Google Scholar, 20Kim D.H. Sladek C.D. Aguadovelasco C. Mathiasen J.R. J. Physiol. (Lond.). 1995; 484: 643-660Crossref Scopus (86) Google by intracellular acidosis. The by which TREK-1 a of the toward positive to channel opening at atmospheric internal acidosis. The acidic of TREK-1 was in whole cell by by and and that channel TREK-1 is the only cloned K+ channel to opened by intracellular acidosis. TRAAK is sensitive to stretch mm F. Fosset M. Lesage F. Lazdunski M. Honoré E. J. Biol. Chem. 1999; 274: 1381-1387Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar) with TREK-1 mm It is also sensitive to pHi is a major between the two channels, which used to a and K+ channel to TREK-1 than to major between TREK-1 and TRAAK is the of by cAMP (7Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (393) Google Scholar). of in the carboxyl terminus of TREK-1 is for the (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar). The that intracellular acidosis TREK-1 opening an with the A phosphorylation which is present in the TRAAK structure, is which lacks and is sensitive to by low and that the pHi-sensitive region of TREK-1 is in the carboxyl-terminal region between and in carboxyl-terminal region by stretch, and critical for channel (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar). The sensitivity to pHi is to TRAAK the carboxyl terminus of TREK-1 is with TRAAK, that the region between Δ46 and the TMS is and to pH of the carboxyl terminus of TREK-1 show that as well as mechano-gating is that the whole to is involved in acidic and stretch and that acids TREK-1 is by a of mechanical as stretch, and and by a of including cAMP-dependent and acidic (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar, 3Patel A.J. Honoré E. Lesage F. Fink M. Romey G. Lazdunski M. Nature Neurosci. 1999; 2: 422-426Crossref PubMed Scopus (564) Google Scholar). TREK-1 is an of mechanical of TREK-1 is by intracellular acidosis, that a to of the sensitivity to TREK-1 an physiological in the and physiological of TREK-1 are stretch, and that intracellular cAMP (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar). It is that of TREK-1 by acidification of the intracellular is an important physiological variations pHi Neurosci. Res. 1996; PubMed Scopus Google Scholar). an is of the important of types of K+ channels N. 1993; Scopus Google Scholar, M. J. Pharmacol. Scholar). been well for the conductance K+ channels channels of the as well as for K+ channels C. C. Lazdunski M. A. 1995; PubMed Scopus Google Scholar, C. C. Lazdunski M. A. 1993; PubMed Scopus Google Scholar, J.R. Lazdunski M. J. 1997; PubMed Scopus Google Scholar). a of the to from channels is hyperpolarization. the cell membrane from the of channel and the channel by It been well the of intracellular and the of intracellular in the of channels N. 1993; Scopus Google Scholar, M. J. Pharmacol. Scholar, M. J.R. R.D. H. Lazdunski M. J. Biol. Chem. 1988; Full Text PDF PubMed Google Scholar, A. A. Kurachi Y. J. Physiol. 1995; PubMed Google Scholar, J. Physiol. Google Scholar). by of the is in tissues the channel is expressed as in the heart brain M. J. Pharmacol. Scholar). In of intracellular which in as brain heart ischemia, opening of TREK-1 channel a similar TREK-1 channels in the channel in with and which also A.J. Lazdunski M. Honoré E. J. Neurosci. 1998; 18: PubMed Google the of intracellular acidification on the of the TREK-1 channel (2Patel A.J. Honoré E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (527) Google Scholar). in heart and brain is with a major K+ efflux N. 1993; Scopus Google Scholar, M. J. Pharmacol. Scholar, J. 1997; 100: PubMed Scopus Google Scholar). efflux is to K+ channels that open these N. 1993; Scopus Google M. J. Pharmacol. Scholar). of of channels efflux J. 1997; 100: PubMed Scopus Google Scholar, P. Lazdunski M. Res. 1990; Scopus Google Scholar). TREK-1 channels thus an important for K+ are to M. and D. for