Ca2+ Selectivity and Fatty Acid Specificity of the Noncapacitative, Arachidonate-regulated Ca2+ (ARC) Channels

The arachidonate-regulated, Ca2+-selective ARC channels represent a novel receptor-activated pathway for the entry of Ca2+ in nonexcitable cells that is entirely separate from the widely studied store-operated, Ca2+ release-activated Ca2+channels. Activation of ARC channels occurs specifically at the low agonist concentrations typically associated with oscillatory Ca2+ signals and appears to provide the predominant mode of Ca2+ entry under these conditions (Mignen, O., Thompson, J. L., and Shuttleworth, T. J. (2001)J. Biol. Chem. 276, 35676–35683). In this study we demonstrate that ARC channels are present in a variety of different cell types including both cell lines and primary cells. Examination of their pharmacology revealed that currents through these channels are significantly inhibited by low concentrations (< 5 μm) of Gd3+, are unaffected by 100 μm2-aminoethyoxydiphenyl borane, and are not activated by the diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol (100 μm). Their selectivity for Ca2+ was assessed by determining the EC50 for external Ca2+ block of the monovalent currents observed in the absence of external divalent cations. The value obtained (150 nm) indicates that the Ca2+ selectivity of ARC channels is extremely high. Examination of the ability of various fatty acids, including arachidonic acid, to activate the ARC channels demonstrated that activation does not reflect any nonspecific membrane fluidity or detergent effects, shows a high degree of specificity for arachidonic acid over other fatty acids (especially monounsaturated and saturated fatty acids), and is independent of any arachidonic acid metabolite. Moreover, studies using the charged analogue arachidonyl coenzyme A demonstrate that activation of the ARC channels reflects an action of the fatty acid specifically at the internal face of the plasma membrane. Whether this involves a direct action of arachidonic acid on the channel protein itself or an action on some intermediary molecule is, at present, unclear. The arachidonate-regulated, Ca2+-selective ARC channels represent a novel receptor-activated pathway for the entry of Ca2+ in nonexcitable cells that is entirely separate from the widely studied store-operated, Ca2+ release-activated Ca2+channels. Activation of ARC channels occurs specifically at the low agonist concentrations typically associated with oscillatory Ca2+ signals and appears to provide the predominant mode of Ca2+ entry under these conditions (Mignen, O., Thompson, J. L., and Shuttleworth, T. J. (2001)J. Biol. Chem. 276, 35676–35683). In this study we demonstrate that ARC channels are present in a variety of different cell types including both cell lines and primary cells. Examination of their pharmacology revealed that currents through these channels are significantly inhibited by low concentrations (< 5 μm) of Gd3+, are unaffected by 100 μm2-aminoethyoxydiphenyl borane, and are not activated by the diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol (100 μm). Their selectivity for Ca2+ was assessed by determining the EC50 for external Ca2+ block of the monovalent currents observed in the absence of external divalent cations. The value obtained (150 nm) indicates that the Ca2+ selectivity of ARC channels is extremely high. Examination of the ability of various fatty acids, including arachidonic acid, to activate the ARC channels demonstrated that activation does not reflect any nonspecific membrane fluidity or detergent effects, shows a high degree of specificity for arachidonic acid over other fatty acids (especially monounsaturated and saturated fatty acids), and is independent of any arachidonic acid metabolite. Moreover, studies using the charged analogue arachidonyl coenzyme A demonstrate that activation of the ARC channels reflects an action of the fatty acid specifically at the internal face of the plasma membrane. Whether this involves a direct action of arachidonic acid on the channel protein itself or an action on some intermediary molecule is, at present, unclear. Ca2+ release-activated Ca2+ 2-aminoethyoxydiphenyl borate 1-oleoyl-2-acetyl-sn-glycerol current through ARC channels N-methyl-d-glucamine magnesium nucleotide-regulated metal Mg2+-inhibited cation eicosatetraynoic acid arachidonyl coenzyme A human embryonic kidney arachidonate-regulated Ca2+ rat basophilic leukemia N-(2-hydroxyethyl)ethylenediaminetriacetic acid picofarad The generation and shaping of [Ca2+]i signals in nonexcitable cells are profoundly influenced by the receptor-activated entry of Ca2+. At high agonist concentrations, this entry determines the sustained elevated level of [Ca2+]i achieved after the inositol 1,4,5-trisphosphate-dependent discharge of the internal agonist-sensitive Ca2+ stores. It is also responsible for the refilling of those stores on termination of the signal (1Putney Jr., J.W. Cell Calcium. 1990; 11: 611-624Crossref PubMed Scopus (1261) Google Scholar). At lower agonist concentrations the induced entry of Ca2+ acts, along with generated inositol 1,4,5-trisphosphate, to initiate and/or drive the characteristic oscillatory changes in [Ca2+]igenerally observed and to modulate their frequency (2Kawanishi T. Blank L.M. Harootunian A.T. Smith M.T. Tsien R.Y. J. Biol. Chem. 1989; 264: 12859-12866Abstract Full Text PDF PubMed Google Scholar, 3Rooney T.A. Sass E.J. Thomas A.P. J. Biol. Chem. 1990; 265: 10792-10796Abstract Full Text PDF PubMed Google Scholar, 4Bootman M.D. Young K.W. Young J.M. Moreton R.B. Berridge M.J. Biochem. 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Nature. 1992; 355: 353-356Crossref PubMed Scopus (1491) Google Scholar, 9Zweifach Scopus Google Scholar). are low channels whose is independent of entirely dependent on of internal Ca2+ stores M. Penner R. J. PubMed Scopus Google Scholar, Penner R. PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar). or at conductances described in a variety of different cell Their and of unclear. the of store-operated Ca2+ that for the receptor-activated entry of Ca2+ in various cells. In a Ca2+ entry pathway that is independent of and is by receptor-activated in arachidonic acid in a variety of different cell types T.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Cell Calcium. PubMed Scopus Google Scholar, T.J. Thompson J.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, L.M. J. 1999; PubMed Scopus Google Scholar). The this novel in cells described T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and the arachidonate-regulated Ca2+ studies that ARC channels and channels including selectivity for a and T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). this that ARC and channels represent entirely distinct conductances with several the most of is that activation of the ARC channels is entirely independent of T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, T.J. Thompson J.L. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to the that ARC and channels represent Although for the store-operated entry of Ca2+ on the of the entry in cell types appears to cation conductances that are distinct from the Ca2+-selective the the various arachidonic Ca2+ entry that described may also reflect the of different is of for the of a pathway in cell to be of the pathway in cell In the present we first the of ARC channels in a of cell types and demonstrated that appears to be a widely Examination of to store-operated and in various cells revealed that are of and of in the of ARC and channels in and the of the ARC channels is we to and those and that this novel and from other channels that may be present, in the cell or in different cell this we on the of ARC their selectivity for Ca2+ and their specificity for arachidonic acid for from the human embryonic kidney cell with the human from of in with and in a at T.J. Thompson J.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). basophilic leukemia and cells obtained from the cells in the the cells was for the and cells in with and from the cell from of in with and cells from by with and described by T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). cells on that the of a at of currents using an described T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of with internal currents using to from a of by using from to or by to a of and at or at the and at the and at obtained cell activation and for of current in the external by of through the of at The the The Ca2+ of this was to be 100 with R. Cell Biol. PubMed Scopus Google Scholar). The the the the of monovalent currents by external Ca2+ and the was Ca2+ or was to this to a of concentrations from to 100 or using Ca2+ concentrations the external was with In these the the to any from the channels for The Ca2+ of this was to be 100 with of the Ca2+ and and of EC50 was using are cell of changes in described T.J. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). eicosatetraynoic acids, and 1-oleoyl-2-acetyl-sn-glycerol was obtained from other and from Although an arachidonic entry of described in a variety of different to the of the ARC channels for cells with the human T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). It these channels are also to provide the for this mode of entry of Ca2+ in other cell we a of different cells for the of arachidonic Ca2+-selective conductances the of ARC to a in the cell types including and cells In these currents activated on of arachidonic acid to the The Ca2+ current under conditions at from in cells to in cells. currents the associated with ARC channels T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google including by absence of any most an activation that was specifically dependent on low concentrations of arachidonic acid and entirely independent of currents through the ARC channels of the by the store-operated and the conductances of the or absence of T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, T.J. of Cell Scholar). currents through ARC channels be by their on arachidonic acid for activation and their from is to to Ca2+ entry In this several studies of the and the a to Ca2+ entry and store-operated at and at 100 are typically the capacitative entry of Ca2+ in a variety of different cell types L.M. J. 1999; PubMed Scopus Google Scholar, L.M. J. Jr., J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google with the that these not Ca2+ entry are on studies of Ca2+ entry using and their on the ARC channels the of and on the Ca2+ currents through ARC channels activated by arachidonic The that a of Ca2+ currents through the ARC channels The of this at and to At the currents to any At a of 5 inhibited currents through the ARC channels The of on Ca2+ entry through the ARC channels was in of arachidonic in Ca2+ for concentrations to block currents through channels in various cell types M.D. J. PubMed Scopus Google Scholar, R.B. Biochem. J. PubMed Scopus Google Scholar, M. J. PubMed Scopus Google Scholar). In of 100 on ARC currents that activated by of arachidonic acid μm) of also to the ability of arachidonic acid to activate the ARC that at a that to currents through channels in several cell types, on the Ca2+ currents through the ARC Although the of both ARC channels and channels is widely that for the are the of of the of and to be activated in a that is independent of involves an action of diacylglycerol that is independent of the activation of and be by diacylglycerol T. M. T. Nature. 1999; PubMed Scopus Google Scholar, T. R. T. T. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the of a activation of the ARC was to activate ARC of (100 μm) to cells to activate ARC current at was of a was not of any with the channels the of arachidonic acid μm) a activation ARC current at The obtained demonstrate that ARC channels are to the channels of and of mast ARC channels are Ca2+-selective with currents through the ARC channels are dependent on the of external a at membrane and a significantly T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Moreover, of with on the observed a for under to other Ca2+-selective including both Ca2+ channels and of divalent a to monovalent through ARC channels T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). on study of this in Ca2+ this is believed to reflect the of a the channel J. PubMed Scopus Google Scholar, Tsien Nature. PubMed Scopus Google Scholar). of this by Ca2+ the of monovalent and this is Although these a for these different channel types, provide on their selectivity to in the selectivity of these channels for be is by determining the of the Ca2+ responsible for the of monovalent through the this for ARC channels by determining the of the monovalent currents in cells at different external It be that that studies on the monovalent through channels significantly by the of an that is activated in the absence of internal the so-called or channels Penner R. J. PubMed Scopus Google Scholar, M. J. PubMed Scopus Google Scholar). In we from conductances the of the monovalent currents through ARC channels was unaffected by of internal T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google or the using the internal are Thompson J.L. T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to be that of monovalent currents through ARC channels in the present study not to from channels the of the internal was to for these of these the monovalent current at internal in the absence of external divalent is by and to at is the Ca2+ current at the in the of external divalent cations. current is to that T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, T.J. of Cell for the ARC channels and from the of for currents through channels in various cell types T.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M.D. J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). these the of the arachidonic monovalent current was at a of different external Ca2+ concentrations The for the monovalent currents at are in to at the different in on a single the current obtained not be to any value at external from different Although this in the external Ca2+ inhibited the monovalent ARC current in a with a EC50 of on the that this reflects the of Ca2+ to a monovalent in the the a Ca2+ for this of at an internal a we also a of the ability of external to block the monovalent current through ARC channels in the absence of external Ca2+ with external inhibited the monovalent current in a with a EC50 at of that with Ca2+. It be that be to that this reflects the for Ca2+ and of the in the channel is from that Ca2+ and to the or the of block of monovalent is the for Ca2+ and the of ARC channels that from the other Ca2+-selective channels is that their activation is entirely dependent on the or of arachidonic this the ability of arachidonic acid to activate the Ca2+ current through the ARC channels was at different concentrations of the fatty The obtained that currents at be obtained with concentrations of arachidonic acid low the of the currents at low concentrations, the characteristic ARC channel of a of by most the absence of any of arachidonic acid not is that the fatty acid to at concentrations J. Biol. Chem. 1992; Full Text PDF PubMed Google the of on the membrane. In the of nonspecific on membrane are at elevated we that concentrations of arachidonic acid conductances of currents reflect the of a of the of the cell membrane. Thompson and T. J. Shuttleworth, acid is a fatty acid and other on membrane by with or by of the of the membrane in the are of these on membrane are induced by a variety of including different fatty acids, and are nonspecific in the fatty acid specificity of the activation of ARC channels we the ability of a of different fatty acids at μm) to activate ARC at the saturated fatty acid, acid and the monounsaturated fatty acid, acid to current was not of any with the ARC channels in the of arachidonic acid in the of a ARC of and that the activation of ARC is a to the fatty this a of different fatty acids including both and with different and of was for their ability to fatty acid was at a of The fatty acid acid a activation of ARC at to a value of or of the value for arachidonic the fatty acids, acid a to a value of or of the arachidonic value of acid was significantly in a current of or of the arachidonic in arachidonic acid on cell is a of the cell a variety of of are to in cells. studies using and that the of arachidonic acid on the entry of Ca2+ reflect the of the fatty acid itself and not of T.J. 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Full Text Full Text PDF PubMed Scopus Google that the agonist at low concentrations, specifically the ARC channels in a dependent on the generation of arachidonic acid via the action of a It most that the activation of the channel is dependent on of arachidonic for the ARC channels with arachidonic acid in the involves the of the fatty acid to the external of the arachidonic acid is to the plasma Full Text PDF PubMed Scopus (68) Google we that the arachidonic acid to of this we of the arachidonic acid molecule a charged that in the molecule to the of the membrane to is Biochem. 1992; PubMed Scopus Google Scholar). the ability of and to of in the in the activation of current at that of the The value of this current was at that the value for ARC currents activated under conditions by the of the μm) of arachidonic acid at 5 the of the current and a significantly 5 was to the ARC current activated by of arachidonic In of the of to the currents at that from and It be that the the internal of that be in the with the that of the cell to this on the we that internal stores of in an activation of we the of the current induced by internal in the of (100 μm) in the demonstrated under the conditions of the of a of any from the of channels in current The of that (100 μm) was on the of current by internal at 5 that activation of channels not arachidonic Ca2+ entry described in a variety of different including cells T.J. 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The of ARC channels the various Ca2+ entry channels of nonexcitable cells is their on arachidonic acid for demonstrated that this activation occurs at concentrations of arachidonic acid and concentrations are the of for the of the responsible for the of the fatty acid and in cells. is several fatty acids including arachidonic acid to the and of different channels in various Jr., Full Text PDF PubMed Scopus Google and PubMed Scopus Google of these are at high At concentrations, a variety of nonspecific on the or of the cell membrane are to the of fatty acids in their cell with on membrane Moreover, the of fatty acids on from the of through 1989; PubMed Scopus Google Scholar). The that nonspecific are not in the observed ability of arachidonic acid to activate ARC the concentrations of arachidonic acid to activate ARC are significantly the for this fatty acid in J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). Moreover, nonspecific also be with saturated fatty acids, acid to activate to changes in membrane is that changes from an the in the of of the membrane the of this is and is influenced by other including the of the and the Smith PubMed Scopus Google Scholar). In the we that acid was significantly an of ARC was acid that the a on membrane fluidity of the of an In M. 1992; PubMed Scopus Google that is arachidonic acid in membrane that was in the that the action of arachidonic acid on the ARC channels is not a of any nonspecific of the of the including changes in membrane in the channel is Moreover, the demonstrated ability of arachidonic acid at ARC shows that the activation of the ARC channels is not dependent on the generation of any of arachidonic the activation of the ARC channels from a action of the fatty acid itself and not of any metabolite. The that the activation of the ARC channels is a to the fatty to be the or the of and the ability to activate acid is the of fatty acid are the and the of acid a acid a to of that with arachidonic Moreover, the ability of to an of the various that arachidonic acid is a of to arachidonic is significantly in ability to ARC arachidonic acid It that the activation of ARC channels a high degree of specificity for arachidonic the obtained from the studies using the arachidonic acid revealed that activation of ARC involves an action of the fatty acid or at the face the of the membrane. Whether this involves a direct action of the fatty acid on the channel protein itself or an action on some intermediary molecule is, at present, that any a high degree of In this is that arachidonic acid the of a with of the a and the other a by PubMed Scopus Google this of arachidonic acid to with protein the by fatty acids is by the obtained using In this the of the arachidonic acid molecule is by the coenzyme A the of the is In we that ARC channels represent a novel of the of Ca2+ entry channels that Ca2+ and the on the ability of external Ca2+ to block monovalent cation through the we that the ARC channels are the most Ca2+-selective of these channel also that current widely to the of and ARC channels are not the of the ARC channels is that their activation is dependent on arachidonic acid and is entirely independent of ARC channels are not the Ca2+ channels whose is influenced by arachidonic in J. J. 1996; PubMed Scopus Google and both and Ca2+ channels in various J. PubMed Scopus Google are inhibited by low concentrations of arachidonic acid, the to with the different channel on the that the activation of ARC channels shows a high degree of specificity for arachidonic acid over other fatty acids (especially monounsaturated and saturated fatty Moreover, this activation involves action of the fatty acid at an on the channel itself or on some intermediary that ARC channels are widely in different cell types indicates that these channels are for the for the arachidonic entry of Ca2+ that described in a variety of different cells. to this is that this entry is through a Ca2+-selective Their demonstrated high selectivity for Ca2+ that entry is through a cation pathway in ARC channels are to be for and and for