Ca2+-independent Phospholipase A2-dependent Gating of TRPM8 by Lysophospholipids

Abstract

TRPM8 represents an ion channel activated by cold temperatures and cooling agents, such as menthol, that underlies the cold-induced excitation of sensory neurons. Interestingly, the only human tissue outside the peripheral nervous system, in which the expression of TRPM8 transcripts has been detected at high levels, is the prostate, a tissue not exposed to any essential temperature variations. Here we show that the TRPM8 cloned from human prostate and heterologously expressed in HEK-293 cells is regulated by the Ca2+-independent phospholipase A2 (iPLA2) signaling pathway with its end products, lysophospholipids (LPLs), acting as its endogenous ligands. LPLs induce prominent prolongation of TRPM8 channel openings that are hardly detectable with other stimuli (e.g. cold, menthol, and depolarization) and that account for more than 90% of the total channel open time. Down-regulation of iPLA2 resulted in a strong inhibition of TRPM8-mediated functional responses and abolished channel activation. The action of LPLs on TRPM8 channels involved either changes in the local lipid bilayer tension or interaction with the critical determinant(s) in the transmembrane channel core. Based on this, we propose a novel concept of TRPM8 regulation with the involvement of iPLA2 stimulation. This mechanism employs chemical rather than physical (temperature change) signaling and thus may be the main regulator of TRPM8 activation in organs not exposed to any essential temperature variations, as in the prostate gland. TRPM8 represents an ion channel activated by cold temperatures and cooling agents, such as menthol, that underlies the cold-induced excitation of sensory neurons. Interestingly, the only human tissue outside the peripheral nervous system, in which the expression of TRPM8 transcripts has been detected at high levels, is the prostate, a tissue not exposed to any essential temperature variations. Here we show that the TRPM8 cloned from human prostate and heterologously expressed in HEK-293 cells is regulated by the Ca2+-independent phospholipase A2 (iPLA2) signaling pathway with its end products, lysophospholipids (LPLs), acting as its endogenous ligands. LPLs induce prominent prolongation of TRPM8 channel openings that are hardly detectable with other stimuli (e.g. cold, menthol, and depolarization) and that account for more than 90% of the total channel open time. Down-regulation of iPLA2 resulted in a strong inhibition of TRPM8-mediated functional responses and abolished channel activation. The action of LPLs on TRPM8 channels involved either changes in the local lipid bilayer tension or interaction with the critical determinant(s) in the transmembrane channel core. Based on this, we propose a novel concept of TRPM8 regulation with the involvement of iPLA2 stimulation. This mechanism employs chemical rather than physical (temperature change) signaling and thus may be the main regulator of TRPM8 activation in organs not exposed to any essential temperature variations, as in the prostate gland. Although TRPM8, a member of the transient receptor potential (TRP) 6The abbreviations used are: TRP, transient receptor potential; PIP2, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; PM, plasma membrane; ER, endoplasmic reticulum; iPLA-2, Ca2+-independent phospholipase A2; LPL, lysophospholipid; ODN, oligodeoxynucleotide; SOC, store-operated Ca2+ channel(s); TG, thapsigargin; pF, picofarads; SD, store-dependent; store-independent; CaM, calmodulin; AA, arachidonic acid; BEL, bromoenol lactone; LPC, lysophosphatidylcholine; LPI, lysophosphatidylinositol; CPZ, chlorpromazine; IP3, inositol 1,4,5-trisphosphate. channel family, was originally cloned from the prostate (1Tsavaler L. Shapero M.H. Morkowski S. Laus R. Cancer Res. 2001; 61: 3760-3769PubMed Google Scholar), recent studies have firmly established its function as a cold/menthol receptor in sensory neurons (2McKemy D.D. Neuhausser W.M. Julius D. Nature. 2002; 416: 52-58Crossref PubMed Scopus (2066) Google Scholar, 3Peier A.M. Moqrich A. Hergarden A.C. Reeve A.J. Andersson D.A. Story G.M. Earley T.J. Dragoni I. McIntyre P. Bevan S. Patapoutian A. Cell. 2002; 108: 705-715Abstract Full Text Full Text PDF PubMed Scopus (1810) Google Scholar). Thus, an outstanding problem heightened by a significant TRPM8 up-regulation in several tumors (prostate, lung, breasts, skin) concerns the whole spectrum of the physiological and pathophysiological roles of TRPM8 in those tissues devoid of any significant temperature variations. Revealing possible alternative molecular events leading to TRPM8 activation at constant temperature would undoubtedly help to uncover other TRPM8 functions beyond the cold sensation. Recently, a model ascribing TRPM8 activation to cold/menthol-induced shifts in the channel voltage dependence toward physiological membrane potentials has been proposed (4Voets T. Droogmans G. Wissenbach U. Janssens A. Flockerzi V. Nilius B. Nature. 2004; 430: 748-754Crossref PubMed Scopus (818) Google Scholar). Although attractive in its explanation of the temperature sensitivity, this model seems to be insufficient to account for TRPM8 activation in those tissues that are not exposed to any essential temperature variations, such as prostate. Moreover, prominent rundown of TRPM8 activity in excised patches (4Voets T. Droogmans G. Wissenbach U. Janssens A. Flockerzi V. Nilius B. Nature. 2004; 430: 748-754Crossref PubMed Scopus (818) Google Scholar, 5Liu B. Qin F. J. Neurosci. 2005; 25: 1674-1681Crossref PubMed Scopus (272) Google Scholar) raised a possibility that some endogenous ligands might be necessary for channel activation. Phosphatidylinositol 4,5-bisphosphate (PIP2) has recently been found to be such a factor, since it was capable not only of restoring menthol-activated TRPM8 current after its rundown in excised patches but also of activating the current independently of menthol (5Liu B. Qin F. J. Neurosci. 2005; 25: 1674-1681Crossref PubMed Scopus (272) Google Scholar, 6Rohacs T. Lopes C.M. Michailidis I. Logothetis D.E. Nat. Neurosci. 2005; 8: 626-634Crossref PubMed Scopus (504) Google Scholar). This would suggest the importance of this endogenous lipid signaling in sustaining the TRPM8 function. Notably, high concentrations of diC8 PIP2 (e.g. 500 μm) allowed channel opening even at 32-37 °C (6Rohacs T. Lopes C.M. Michailidis I. Logothetis D.E. Nat. Neurosci. 2005; 8: 626-634Crossref PubMed Scopus (504) Google Scholar). The functional importance of the PIP2-dependent TRPM8 gating has thus become evident in the cold sensation, since any of the well known PIP2 depletion scenarios (e.g. activation of Gq/11-PLC-coupled receptors or Ca2+-dependent activation of some PLC isoforms) would limit TRPM8 activation by shifting its gating toward lower temperatures or higher voltages. However, the possibility of channel activation (rather than desensitization) with the involvement of PIP2 seems more remote. Experimentally, this can be achieved by co-expression of enzymes, which catalyze PIP2 formation (e.g. PIP5K), and this maneuver indeed significantly attenuated TRPM8 desensitization (6Rohacs T. Lopes C.M. Michailidis I. Logothetis D.E. Nat. Neurosci. 2005; 8: 626-634Crossref PubMed Scopus (504) Google Scholar), suggesting a physiological relevance of this mechanism in connection with the (over)expression of PIP2-forming enzymes. PIP2 replenishment also requires Ca2+ influx (the mechanism remains unknown), and TRPM8 desensitization is also known to be accelerated by Ca2+ withdrawal. Since the prostate has not been shown to be exposed to any temperature variations, the issue of physiological TRPM8 activation in the prostate is even less clear. The problem is complicated by the fact that TRPM8 may be localized not only in the plasma membrane (PM), but also in the membrane of the endoplasmic reticulum (ER), where it can operate as a Ca2+ release channel (7Zhang L. Barritt G.J. Cancer Res. 2004; 64: 8365-8373Crossref PubMed Scopus (270) Google Scholar, 8Tsuzuki K. Xing H. Ling J. Gu J.G. J. Neurosci. 2004; 24: 762-771Crossref PubMed Scopus (109) Google Scholar, 9Thebault S. Lemonnier L. Bidaux G. Flourakis M. Bavencoffe A. Gordienko D. Roudbaraki M. P. R. J. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). Ca2+ depletion is known to be with the of the Ca2+-independent phospholipase A2 (iPLA2) J. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar), which the of lysophospholipids I. M. 2002; PubMed Scopus Google Scholar, M. 2004; PubMed Scopus Google Scholar) (LPLs), lipid which in the activation of a of ion channels A.J. M. 2001; PubMed Scopus Google Scholar, F. A.J. F. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar, T. P. Nat. 2004; PubMed Scopus Google Scholar), the channel A.M. J. F. J. K. J. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). this as well as a potential of lipid in the TRPM8 in the we or not iPLA2 a in TRPM8 functions the mechanism of this would of TRPM8 and from human prostate was cloned from of human prostate by a for TRPM8 as and The was by a and with and with was with the The and was and and by was by and the was of HEK-293 HEK-293 cells as from The cells in a and with of after cells to for and and for the of the TRPM8 channel expression and and of to be the was in the functional iPLA2 activity of iPLA2 was as in the T. P. Nat. 2004; PubMed Scopus Google Scholar) a originally for phospholipase A2 The activity of iPLA2 was expressed in of total iPLA2 was on the bromoenol iPLA2 activity iPLA2 activity iPLA2 activity with iPLA2 was for the iPLA2 activity activity with and in the whole and of the the The of the from with the was for the whole and for the channel the whole was for by at or and at with the was with the with the cells in a with an of for to the potential to the was with The was with to temperature and the was used with the temperature the The a temperature of at of Ca2+ was the as F. Roudbaraki M. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar). and changes as for current from cells and the and channel on the of the not since or more channels in a membrane as of the and with the of the and for levels, that less than where is (e.g. for a with the openings of the channel to in at potentials in a of where openings be activity was expressed as where represents the of channels in the and represents open from expressed as the was significant was and from for and which from and iPLA2 depletion was by cells for to with either at the iPLA2 and to at a or by to the The used in studies the for and TRPM8, with TRPM8 by of the The used was This is at of the TRPM8 with μm) for at °C in the by a in the was in as and was to the by to the was HEK-293 cells human TRPM8 of a cells used as TRPM8 by studies have established of TRPM8 in the as well as in (7Zhang L. Barritt G.J. Cancer Res. 2004; 64: 8365-8373Crossref PubMed Scopus (270) Google Scholar, 8Tsuzuki K. Xing H. Ling J. Gu J.G. J. Neurosci. 2004; 24: 762-771Crossref PubMed Scopus (109) Google Scholar, 9Thebault S. Lemonnier L. Bidaux G. Flourakis M. Bavencoffe A. Gordienko D. Roudbaraki M. P. R. J. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). The functional of the and of the heterologously expressed TRPM8 was Ca2+ and the that of Ca2+ release from Ca2+ in to with the of cells to menthol μm) in the of Ca2+ a transient to Ca2+ release from the ER, by a to in the of menthol to the of Ca2+ Ca2+ release Ca2+ be detected in to menthol in cells open thus suggesting that of are to TRPM8 The in that TRPM8 functions as a menthol-activated Ca2+ release channel in Thus, Ca2+ in to menthol may from the activation of potential endogenous store-operated Ca2+ channels of HEK-293 cells as well as TRPM8 which in studies have been shown to be (2McKemy D.D. Neuhausser W.M. Julius D. Nature. 2002; 416: 52-58Crossref PubMed Scopus (2066) Google Scholar, 3Peier A.M. Moqrich A. Hergarden A.C. Reeve A.J. Andersson D.A. Story G.M. Earley T.J. Dragoni I. McIntyre P. Bevan S. Patapoutian A. Cell. 2002; 108: 705-715Abstract Full Text Full Text PDF PubMed Scopus (1810) Google Scholar). we to with of menthol, and of which was used as the acting independently of TRPM8 the inhibition of Ca2+ was used as a F. Roudbaraki M. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar). that the of μm) in the not with the of a known to induce activation T.J. J. Full Text Full Text PDF PubMed Scopus Google to depletion in but it Ca2+ of suggesting a of the endogenous The in cells a Ca2+ Moreover, of menthol μm) the Ca2+ in cells an Ca2+ which to the as menthol and can only be with the depletion is to a activation of the TRPM8 and menthol can TRPM8 that action on TRPM8 channel and a functional of depletion to we of and membrane in and of TRPM8-mediated current with store-operated current activated in to or depletion its was to be since even at not F. Roudbaraki M. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar, F. Lemonnier L. S. G. R. J. 2004; Full Text Full Text PDF PubMed Scopus Google we used The of Ca2+ also rundown as well as desensitization of TRPM8-mediated current (2McKemy D.D. Neuhausser W.M. Julius D. Nature. 2002; 416: 52-58Crossref PubMed Scopus (2066) Google Scholar). The in cells by temperature and menthol dependence as well as by those that for the TRPM8, as channel (2McKemy D.D. Neuhausser W.M. Julius D. Nature. 2002; 416: 52-58Crossref PubMed Scopus (2066) Google Scholar, 3Peier A.M. Moqrich A. Hergarden A.C. Reeve A.J. Andersson D.A. Story G.M. Earley T.J. Dragoni I. McIntyre P. Bevan S. Patapoutian A. Cell. 2002; 108: 705-715Abstract Full Text Full Text PDF PubMed Scopus (1810) Google Scholar, T. Droogmans G. Wissenbach U. Janssens A. Flockerzi V. Nilius B. Nature. 2004; 430: 748-754Crossref PubMed Scopus (818) Google Scholar). at temperature but not which to be at this temperature by menthol μm) and by to °C in the of menthol with the cooling to and menthol μm) the activation voltage of the TRPM8-mediated current by and any in the which was in evident from the of the or menthol-activated membrane in cells was at suggesting significant expression of the TRPM8 with this, the patches more than channel also an of channels at a high that channel activity was as for This was by the of the current and by the which was to the (2McKemy D.D. Neuhausser W.M. Julius D. Nature. 2002; 416: 52-58Crossref PubMed Scopus (2066) Google Scholar). with of functional TRPM8 and Ca2+ of cells with resulted in a significant current at which was by the as prominent and to potential we to the activation of TRPM8 channels to to the be that the whole rundown in the of with the not the rundown of was even and more constant of suggesting that the may a that is The fact that menthol was to a current than in cells current of for menthol for at and which in was less to that TRPM8 gating by menthol involved and TRPM8 gating by the The of the of TRPM8 gating the whole TRPM8-mediated membrane current to be as the of that is with depletion and that is not the of such a where activation of TRPM8 in cells was in channel from a at of μm) at channel from such patches was to that found in the cold/menthol the of TG, open channel with and a at with the of the involvement of a rather than any action on the channel a physiological the of the TRPM8 activation was the of channel opening at potentials at °C at which not even open be a of channel gating on the voltage was by voltage dependence and after more channel openings which with a to the channel activity of the on the of open that openings to 90% of the total channel open time. Notably, the cooling and menthol, in which only and of the total channel open even at strong Thus, the mechanism to be to TRPM8 activation in tissues not any to the mechanism of the in the TRPM8 on the depletion is known to iPLA2 J. J. J. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar) on the other iPLA2 and of lysophospholipids as the has been in activation T. P. Nat. 2004; PubMed Scopus Google Scholar, T. P. J. Full Text Full Text PDF PubMed Scopus Google Scholar), we on the iPLA2 pathway as a possible of the of this depletion of the from it a capable of arachidonic and of which the the channels in a T. P. Nat. 2004; PubMed Scopus Google Scholar). Thus, the of the iPLA2 was to show iPLA2 activity is by TG, or iPLA2 to the of and TRPM8-mediated and the of lipid lysophospholipids or AA, are capable of TRPM8 activation. with the depletion and iPLA2 J. J. J. 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J. Full Text Full Text PDF PubMed Scopus Google Scholar, T. P. Nat. 2004; PubMed Scopus Google Scholar). we which of is involved in TRPM8 activation this we used channel in patches the to the of the that from a at temperature resulted in a in the TRPM8 channel activity from of in the to of patches This is by PIP2 depletion by lipid in membrane (5Liu B. Qin F. J. Neurosci. 2005; 25: 1674-1681Crossref PubMed Scopus (272) Google Scholar, 6Rohacs T. Lopes C.M. Michailidis I. Logothetis D.E. Nat. Neurosci. 2005; 8: 626-634Crossref PubMed Scopus (504) Google Scholar). However, of μm) or not only the activity but also it significantly the and events action of the as those by cold or menthol, an TRPM8 channel since in the of LPLs capable of activating TRPM8 at potentials toward a physiological relevance of this which is also with Ca2+ of the iPLA2 in cells and The of LPLs in patches to a in TRPM8 temperature and or to the fact that patches (5Liu B. Qin F. J. 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PubMed Scopus Google Scholar). iPLA2 activation has been in menthol has been shown to of prostate cells (7Zhang L. Barritt G.J. Cancer Res. 2004; 64: 8365-8373Crossref PubMed Scopus (270) Google Scholar). it is that of by menthol in to the mechanism may also the Ca2+ with the activation of TRPM8 and channels as a of iPLA2 stimulation. have found that the in the mechanism of TRPM8 activation which are iPLA2 stimulation. is that recently lipid PIP2, has been established as a in TRPM8 channel function (5Liu B. Qin F. J. Neurosci. 2005; 25: 1674-1681Crossref PubMed Scopus (272) Google Scholar, 6Rohacs T. Lopes C.M. Michailidis I. Logothetis D.E. Nat. Neurosci. 2005; 8: 626-634Crossref PubMed Scopus (504) Google Scholar). PIP2 as a for PLC, in to the membrane the inositol and is the acting the The fact that of PLC on TRPM8 PIP2 and activation seems can be roles for the lipid the PIP2 TRPM8 desensitization (6Rohacs T. Lopes C.M. Michailidis I. Logothetis D.E. Nat. 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