ATP applied at a micromolar range activates a native TREK-1-like K+ current in rat ventricular cardiomyocytes via a dual-MAPK cytosolic pathway involving p38 MAPK and p42/44 MAPK.
This study provides the first characterization of a native TREK-1-like potassium current in cardiac cells that is activated by ATP via a dual-MAPK cytosolic pathway.
Living cells exhibit multiple K+ channel proteins; among these is the recently reported atypical two-pore domain K+ channel protein TREK-1. Most K+ currents are modulated by neurohormones and under various pathological conditions. Here, in rat ventricular cardiomyocytes using the whole-cell patch-clamp technique, we characterize for the first time a native TREK-1-like current (ITREK) that is activated by ATP, a purine agonist applied at a micromolar range. This current is sensitive to arachidonic acid, intracellular acidosis, and various K+ current inhibitors. Reverse transcription-polymerase chain reaction reveals the presence of a TREK-1-like mRNA in rat cardiomyocytes that shows 93% identity with mouse TREK-1. ATP effects are greatly attenuated in the presence of arachidonic acid or HCO−3-induced intracellular acidosis. Using a series of inhibitors, we further demonstrate that the ATP-induced stimulation of ITREKimplies the activation of cytosolic phospholipase A2 and the release of arachidonic acid. These events require the simultaneous involvement of p38 MAPK and p42/44 MAPK, respectively, via a cAMP-dependent protein kinase and a tyrosine kinase pathway, whereas the two MAPKs conjugate to activate a mitogen- and stress-activated protein kinase (MSK-1). Our results thus demonstrate the occurrence of a TREK-1-like current in cardiac cells whose activation by purine agonists implies a dual-MAPK cytosolic pathway. Living cells exhibit multiple K+ channel proteins; among these is the recently reported atypical two-pore domain K+ channel protein TREK-1. Most K+ currents are modulated by neurohormones and under various pathological conditions. Here, in rat ventricular cardiomyocytes using the whole-cell patch-clamp technique, we characterize for the first time a native TREK-1-like current (ITREK) that is activated by ATP, a purine agonist applied at a micromolar range. This current is sensitive to arachidonic acid, intracellular acidosis, and various K+ current inhibitors. Reverse transcription-polymerase chain reaction reveals the presence of a TREK-1-like mRNA in rat cardiomyocytes that shows 93% identity with mouse TREK-1. ATP effects are greatly attenuated in the presence of arachidonic acid or HCO−3-induced intracellular acidosis. Using a series of inhibitors, we further demonstrate that the ATP-induced stimulation of ITREKimplies the activation of cytosolic phospholipase A2 and the release of arachidonic acid. These events require the simultaneous involvement of p38 MAPK and p42/44 MAPK, respectively, via a cAMP-dependent protein kinase and a tyrosine kinase pathway, whereas the two MAPKs conjugate to activate a mitogen- and stress-activated protein kinase (MSK-1). Our results thus demonstrate the occurrence of a TREK-1-like current in cardiac cells whose activation by purine agonists implies a dual-MAPK cytosolic pathway. protein kinase A polymerase chain reaction reverse transcription-PCR phospholipase A2 cytosolic PLA2 mitogen-activated protein kinase mitogen- and stress-activated protein kinase thymidine kinase arachidonic acid pertussis toxin acetylcholine deoxynucleotide triphosphates nordihydroguaiaretic acid haloenol lactone suicide substrate focal adhesion kinase MAPK-activated protein kinase The exceptional diversity of K+ currents has physiological significance in the heart, where the various currents underlie distinct phases of action potential repolarization. Recent cloning efforts have identified a large number of pore-forming subunits for K+ channels. They include the voltage-activated, outward rectifying K+ channels (Kv families) and the inward rectifying K+ channels (Kir families) that show a single pore-forming region and six or two transmembrane domains, respectively. More recently, a novel class of K+ channel subunits (TWIK) that possess two pore-forming regions and four transmembrane domains has been cloned and expressed (1Duprat F. Lesage F. Fink M. Reyes R. Heurteaux C. Lazdunski M. EMBO J. 1997; 16: 5464-5471Crossref PubMed Scopus (549) Google Scholar, 2Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (398) Google Scholar, 3Lesage F. Guillemare E. Fink M. Duprat F. Lazdunski M. Romey G. Barhanin J. EMBO J. 1996; 15: 1004-1011Crossref PubMed Scopus (460) Google Scholar, 4Lesage F. Lauritzen I. Duprat F. Reyes R. Fink M. Heurteaux C. Lazdunski M. FEBS Lett. 1997; 402: 28-32Crossref PubMed Scopus (106) Google Scholar). All expressed TWIK-related K+ channels produce instantaneous and noninactivating currents that do not display a voltage-dependent activation threshold. Some show properties of a background K+ current, whereas others are activated by free fatty acids and stretch (2Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (398) Google Scholar, 5Patel A.J. Honore E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (537) Google Scholar) and by intracellular acidosis (6Maingret F. Patel A.J. Lesage F. Lazdunski M. Honore E. J. Biol. Chem. 1999; 274: 26691-26696Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). TREK-1 and TBAK-1 or TASK-1 are expressed in the whole heart (1Duprat F. Lesage F. Fink M. Reyes R. Heurteaux C. Lazdunski M. EMBO J. 1997; 16: 5464-5471Crossref PubMed Scopus (549) Google Scholar, 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, 8Kim D. Fujita A. Horio Y. Kurachi Y. Circ. Res. 1998; 82: 513-518Crossref PubMed Scopus (114) Google Scholar). Whether these proteins carry a physiological ionic current is not yet known in any tissue. Of the purinergic agonists released during ischemia and other pathological conditions, adenosine has been the most extensively studied. However, under similar conditions, ATP is also released into the extracellular space (9Gordon J.L. Biochem. J. 1986; 233: 309-319Crossref PubMed Scopus (1408) Google Scholar, 10Kuzmin A.I. Lakomkin V.L. Kapelko V.I. Vassort G. Am. J. Physiol. 1998; 275: C766-C771Crossref PubMed Google Scholar). Extracellular ATP modulates the inward rectifying K+ currents, IK1 and IK(Ach), and a delayed outward rectifying current in atrial cells (11Matsuura H. Sakaguchi M. Tsuruhara Y. Ehara T. J. Physiol. ( Lond. ). 1996; 490: 659-671Crossref PubMed Scopus (28) Google Scholar, 12Matsuura H. Ehara T. J. Physiol. ( Lond. ). 1997; 503: 45-54Crossref PubMed Scopus (16) Google Scholar). Recently, it was postulated that tyrosine phosphorylation is involved in the enhancement of the delayed rectifier K+ current by ATP in guinea pig ventricular cells (13Matsubayashi T. Matsuura H. Ehara T. Pflugers Arch. 1999; 437: 635-642PubMed Google Scholar). Besides activating ionotropic P2X receptors, purinergic stimulation by ATP might involve several of the multiple metabotropic P2Y receptors found in cardiac cells (14Ralevic V. Burnstock G. Pharmacol. Rev. 1998; 50: 413-492PubMed Google Scholar). P2Y receptors have been shown to be linked to activation of PKA1 (15Puceat M. Bony C. Jaconi M. Vassort G. FEBS Lett. 1998; 431: 189-194Crossref PubMed Scopus (34) Google Scholar), protein kinase C and MAPK (16Puceat M. Hilal-Dandan R. Strulovici B. Brunton L.L. Brown J.H. J. Biol. Chem. 1994; 269: 16938-16944Abstract Full Text PDF PubMed Google Scholar, 17Zheng J.S. Boluyt M.O. O'Neill L. Crow M.T. Lakatta E.G. Circ. Res. 1994; 74: 1034-1041Crossref PubMed Scopus (48) Google Scholar), and TK (18Puceat M. Roche S. Vassort G. J. Cell Biol. 1998; 141: 1637-1646Crossref PubMed Scopus (53) Google Scholar). ATP also activates phospholipase A2 (PLA2) in several tissues (19Bolego C. Ceruti S. Brambilla R. Puglisi L. Cattabeni F. Burnstock G. Abbracchio M.P. Br. J. Pharmacol. 1997; 121: 1692-1699Crossref PubMed Scopus (81) Google Scholar, 20Firestein B.L. Xing M. Hughes R.J. Corvera C.U. Insel P.A. Am. J. Physiol. 1996; 271: F610-F618PubMed Google Scholar, 21Xing M. Insel P.A. J. Clin. Invest. 1996; 97: 1302-1310Crossref PubMed Scopus (102) Google Scholar). In a variety of cell types, PLA2 activation occurs as a result of phosphorylation by MAPKs (22Lin L.L. Wartmann M. Lin A.Y. Knopf J.L. Seth A. Davis R.J. Cell. 1993; 72: 269-278Abstract Full Text PDF PubMed Scopus (1659) Google Scholar, 23Leslie C.C. J. Biol. Chem. 1997; 272: 16709-16712Abstract Full Text Full Text PDF PubMed Scopus (743) Google Scholar). In neutrophils, it was recently reported that inhibitors of p38 MAPK and p42/44 MAPK individually reduced cytosolic PLA2(cPLA2) activity, whereas their combined blockade caused a total inhibition of cPLA2 (24Hazan-Halevy I. Seger R. Levy R. J. Biol. Chem. 2000; 275: 12416-12423Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). Arachidonic acid (AA), which is released by cPLA2 during metabolic inhibition or ischemia, activates a K+ current, IK(AA), in rat neonatal atrial and adult ventricular cells (25Kim D. Clapham D.E. Science. 1989; 244: 1174-1176Crossref PubMed Scopus (270) Google Scholar, 26Kim D. Duff R.A. Circ. Res. 1990; 67: 1040-1046Crossref PubMed Scopus (95) Google Scholar). The channel subunit protein underlying IK(AA) is unknown. We now report a TREK-like K+ current in isolated rat ventricular cells. This current is activated by extracellular ATP via the release of arachidonic acid after cPLA2 activation. The purinergic-dependent activation of cPLA2requires the simultaneous activation of both p38 MAPK and p42/44 MAPK by a cAMP-dependent protein kinase and a tyrosine kinase-dependent pathway, respectively. Ventricular myocytes were isolated from the heart of urethane-anesthetized (2 g/kg, i.p.) Wistar rats as described previously (27Aimond F. Alvarez J.L. Rauzier J.M. Lorente P. Vassort G. Cardiovasc. Res. 1999; 42: 402-415Crossref PubMed Scopus (89) Google Scholar). The heart was first perfused for 5 min at 35 °C with a nominally Ca-free HEPES-buffered solution containing 117 mm NaCl, 5.7 mm KCl, 4.4 mmNaHCO3, 1.5 mm KH2PO4, 1.7 mm MgCl2, 21 mm HEPES, 11 mm glucose, 20 mm taurine and then perfused for 40 min with the same solution plus 30 μm Ca2+and 1.2 mg/ml collagenase (CLS4; Worthington). The heart was then gently dissociated through the bore of a large-tip pipette, followed by two decantations to separate dead cells. The cells were then suspended in HEPES buffer with 1 mm Ca2+ and 0.5% bovine serum albumin (pH 7.4). The yield of well-striated, cells was of was using the whole-cell patch-clamp at °C was The series and time of were cells to the 1 in which is the current, is the current at the of the and is the of the (2 from a potential of K+ currents were during applied and in from a potential of or from a potential of in as were at with a and using a cell was in a containing the solution mm KCl, mm 1.7 mm MgCl2, mm glucose, and mm was to with whole-cell patch-clamp the cell was to extracellular by it at the of of six a of solution The solution was with μm and to and respectively. The solution mm KCl, mm MgCl2, 5 mm 5 mm mm 11 mm free and 20 mm was with to total K+ were for min in the presence of mm of cardiac cells were for min at °C with 30 μm 40 μm arachidonic acid, or 1 μm with or with inhibitors. was by of acid. the was in and to protein Biochem. 72: PubMed Scopus Google Scholar). The was by and the was of the was for the A protein was to isolated myocytes were with for 20 at were then with to free and for 20 min at The inhibitors were then for 20 min the agonist μm in the was by (22Lin L.L. Wartmann M. Lin A.Y. Knopf J.L. Seth A. Davis R.J. Cell. 1993; 72: 269-278Abstract Full Text PDF PubMed Scopus (1659) Google Scholar). cells were in buffer containing mm mm 1 mm 1 mm MgCl2, and mm with cells were then at for 20 min to separate the and proteins from the cytosolic The was then with buffer mm NaCl, 5 mm and mm with 1 mm mm 1 mm and of MAPK was using the cytosolic whereas was using the proteins from were and the were at °C with the cPLA2 or p38 MAPK and p42/44 MAPK were at a of was using for cPLA2 or for MAPK and to the The were by a the were for 20 min at °C in a buffer containing mm and mm to was from isolated ventricular cells cells were in and was by a P. Biochem. PubMed Scopus Google Scholar, Jaconi Vassort G. M. J. Cell 1999; PubMed Google Scholar). was from 1 of total using of reverse μm and 5 was using a of to to the of mouse TREK-1 number reverse to and in the of mouse was using a 20 at °C for °C to °C for and °C for followed by 20 at a of °C and a of min at was also from of a mouse The were by and the were by of using a and of The of the was by and by two using the same for and a of reverse to the two of the by of were using and was In rat ventricular distinct K+ currents are activate the inward rectifier sensitive to whereas activation of the outward K+ current sensitive to and of the delayed rectifier K+ current sensitive to J.M. Rev. Physiol. 1996; PubMed Scopus Google Scholar). The of 30 μm ATP in both the outward and inward currents that after min 1 The ATP-induced outward current a activation with during the In in the presence of mm the time to was at to the ATP-induced inward current was at and a after current during the first 20 of the applied at the of the inward and outward current a in the inward current 1 The outward current was as a result of a inhibition of The ATP-induced current at the of the a and inward 1 effects were by or ATP in the presence of of whereas the ATP effects were by a not current activation results from ATP activation of ATP activated a K+ current in rat ventricular cells not as it in atrial cells (11Matsuura H. Sakaguchi M. Tsuruhara Y. Ehara T. J. Physiol. ( Lond. ). 1996; 490: 659-671Crossref PubMed Scopus (28) Google Scholar). In the presence of which a large inward current, the further of ATP was to outward and inward currents, not the large inward current 1 these conditions, the ATP-induced current a activation with for both and cells that have been with to the ATP inward and outward currents 1 of the ATP-induced current in the presence of or after show inward and outward with similar potential and 1 ATP activates both a and a current in isolated ventricular myocytes of the In the the properties of the current were known to cardiac K+ currents were to characterize the ATP-induced K+ effects are the outward current at The ATP-induced outward K+ current was in to a of the current, and by and by and at is known to in outward K+ currents in cardiomyocytes (25Kim D. Clapham D.E. Science. 1989; 244: 1174-1176Crossref PubMed Scopus (270) Google Scholar, 26Kim D. Duff R.A. Circ. Res. 1990; 67: 1040-1046Crossref PubMed Scopus (95) Google Scholar, Lakatta E.G. Am. J. Physiol. 1998; 274: Google Scholar) and to activate several two-pore domain K+ channels (2Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (398) Google Scholar). In the presence of ATP further The effects of both ATP and were similar in the presence of and respectively, and inhibitors not The of which is known to intracellular acidosis and activate TREK-1 (6Maingret F. Patel A.J. Lesage F. Lazdunski M. Honore E. J. Biol. Chem. 1999; 274: 26691-26696Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar), the of ATP by activating the K+ current The of ATP was further the ATP-induced K+ current was by extracellular acidosis from to This the current to be by TASK-1 (1Duprat F. Lesage F. Fink M. Reyes R. Heurteaux C. Lazdunski M. EMBO J. 1997; 16: 5464-5471Crossref PubMed Scopus (549) Google Scholar). a inward current, ATP activates a K+ current whose to the recently described two-pore domain TREK-1 or to a TREK-1-like which we to as of the ATP-induced outward K+ current, K+ to or to the ATP-induced current in the mm to or to the ATP-induced current in the mm to or to the ATP-induced current in the mm to or to the ATP-induced current in the mm to or to the ATP-induced current in the mm are expressed in of cells is and for 11 to or to the ATP-induced current in the mm respectively. in a are expressed in of cells is and for 11 We to for the presence of TREK-1 mRNA in rat ventricular cardiomyocytes using to the of the mouse TREK-1 shows from the total of these as as a with the from mouse The rat ventricular 93% identity with TREK-1 M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (425) Google Scholar). activation by ATP also require after PLA2 ventricular myocytes were with a of the This ATP activation of the outward inhibition was not with a of intracellular in with a solution containing a intracellular Ca2+ with 5 mm and Ca2+ ATP a in outward K+ current in of cPLA2 to the as as a in the release of by isolated rat ventricular myocytes These that as a result of cPLA2 activation. of cells with or inhibitors of p38 MAPK or p42/44 MAPK, ATP-induced cPLA2 and activation the effects of ATP and were by the of TK inhibitors as A and and in the of and cAMP-dependent protein kinase the activation of by ATP, whereas the cells with the two release and cPLA2 extracellular ATP is known to by activating the in neonatal rat cardiomyocytes (15Puceat M. Bony C. Jaconi M. Vassort G. FEBS Lett. 1998; 431: 189-194Crossref PubMed Scopus (34) Google Scholar). was by in isolated rat ventricular myocytes after purinergic that by stimulation also M. Bony C. Jaconi M. Vassort G. FEBS Lett. 1998; 431: 189-194Crossref PubMed Scopus (34) Google Scholar). of was the ATP-induced in was by with of cPLA2 and MAPK not of in the ATP was also the the in not of the cells with ATP a of the mitogen- and stress-activated protein kinase the activation of by ATP as as the of of p38 MAPK and p42/44 MAPK that after a time to the ATP activation of both MAPKs p38 MAPK activation by ATP was not by A and not was by the the not the p42/44 MAPK activation by This that and TK activate p38 MAPK and p42/44 MAPK, respectively. p38 MAPK and p42/44 MAPK activation The results demonstrate for the first time the occurrence of a native TREK-1-like purinergic stimulation of cardiomyocytes K+ current after the activation of cPLA2 by a dual-MAPK the expressed TREK-1 current activated by or acidosis, the ATP-induced current in cardiomyocytes is activation and outward and shows to various K+ channel In with identity to the mouse TREK-1 are in the rat ventricular activates several currents which is also activated by intracellular acidosis (6Maingret F. Patel A.J. Lesage F. Lazdunski M. Honore E. J. Biol. Chem. 1999; 274: 26691-26696Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar). Our the activation is or to the of the intracellular C.C. Circ. Res. 2000; PubMed Google Scholar). However, a of is A is under patch-clamp conditions, where the of the cell released and the solution is by 20 mm a inward current (11Matsuura H. Sakaguchi M. Tsuruhara Y. Ehara T. J. Physiol. ( Lond. ). 1996; 490: 659-671Crossref PubMed Scopus (28) Google Scholar), ATP activates the recently described and two-pore domain TREK-1 (2Fink M. Lesage F. Duprat F. Heurteaux C. Reyes R. Fosset M. Lazdunski M. EMBO J. 1998; 17: 3297-3308Crossref PubMed Scopus (398) Google Scholar, 5Patel A.J. Honore E. Maingret F. Lesage F. Fink M. Duprat F. Lazdunski M. EMBO J. 1998; 17: 4283-4290Crossref PubMed Scopus (537) Google Scholar, F. Patel A.J. Lesage F. Lazdunski M. Honore E. J. Biol. Chem. 1999; 274: 26691-26696Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar) or a channel with similar in cardiac This current activation by and intracellular acidosis with IK(AA) reported in rat neonatal atrial cardiomyocytes (25Kim D. Clapham D.E. Science. 1989; 244: 1174-1176Crossref PubMed Scopus (270) Google Scholar, 26Kim D. Duff R.A. Circ. Res. 1990; 67: 1040-1046Crossref PubMed Scopus (95) Google Scholar). was also that was reduced in the presence of most inhibitors of or the other of the MAPK This is in with the in outward current found ATP This current result from a ATP-induced that was in the presence of to the solution from current not be to a of by activation as reported previously M. Duprat F. Lesage F. Reyes R. Romey G. Heurteaux C. Lazdunski M. EMBO J. 1996; 15: 6854-6862Crossref PubMed Scopus (425) Google Scholar) or to a inhibition of channel by E. Barhanin J. B. Lesage F. Lazdunski M. S. A. 1994; PubMed Scopus Google Scholar). 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Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). of the p42/44 MAPK by receptors is tyrosine kinase-dependent tyrosine kinase inhibitors and tyrosine and have been in activation by in cardiac myocytes J. S. EMBO J. 1996; 15: PubMed Scopus Google Scholar). we reported previously that purinergic stimulation activates and to the in the rat heart and cell acidosis (18Puceat M. Roche S. Vassort G. J. Cell Biol. 1998; 141: 1637-1646Crossref PubMed Scopus (53) Google Scholar). with the inhibition of the ATP-induced cPLA2 activation by in the cell Lin L.L. J. Cell PubMed Scopus (425) Google Scholar), in not the ATP effects it the effects of acetylcholine the inward current 1 This that a protein is not involved in pathway, whose to be efforts have been in to the of activation of cPLA2 and the release of cPLA2 from the to the is a for to that require Ca2+ cPLA2 is known to be at Ca2+ found in the of cardiac myocytes (22Lin L.L. Wartmann M. Lin A.Y. Knopf J.L. Seth A. 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Aimond et al. (Fri,) reported a other. ATP was evaluated on Activation of TREK-1-like current (ITREK). ATP applied at a micromolar range activates a native TREK-1-like K+ current in rat ventricular cardiomyocytes via a dual-MAPK cytosolic pathway involving p38 MAPK and p42/44 MAPK.