Key points are not available for this paper at this time.
The TRPV4 calcium-permeable channel was cloned from mouse kidney M-1 cells, and the effect of temperature modulation on channel gating/activation by physical and chemical signals was evaluated. A TRPV4 cDNA construct with a C-terminal V5 epitope was stably transfected into human embryonic kidney (HEK) 293 and Chinese hamster ovary cells resulting in high levels of expression at the plasma membrane. Channel activation was assessed from changes in calcium influx (fura-2 fluorescence measurements) or whole cell currents (patch clamp analysis). At room temperature (22–24 °C), exposure of TRPV4-transfected cells to hypotonic medium (225 mOsm/liter) or a non-protein kinase C (PKC)-activating phorbol ester derivative, 4α-phorbol 12,13-decanoate (100 nm), induces modest channel activation, whereas phorbol 12-myristate 13-acetate (100 nm), a PKC-activating phorbol ester, and shear stress (3–20 dyne/cm2) had minimal or no effect on channel activation. In contrast, at elevated temperatures (37 °C) the channel was rapidly activated by all stimuli. Inhibition of PKC by calphostin C (50 nm) or staurosporine (500 nm) abolished phorbol 12-myristate 13-acetate-induced activation of the channel without affecting the response to other stimuli. Ruthenium red (1 μm) effectively blocked the channel activity by all stimuli. It is concluded that temperature is a critical modulator of TRPV4 channel gating, leading to activation of the channel by a diverse range of microenvironmental chemical and physical signals utilizing a least two transduction pathways, one PKC-dependent and one PKC-independent. The convergence of multiple signals and transduction pathways on the same channel indicate that the channel functions as a molecular integrator of microenvironmental chemical and physical signals. The TRPV4 calcium-permeable channel was cloned from mouse kidney M-1 cells, and the effect of temperature modulation on channel gating/activation by physical and chemical signals was evaluated. A TRPV4 cDNA construct with a C-terminal V5 epitope was stably transfected into human embryonic kidney (HEK) 293 and Chinese hamster ovary cells resulting in high levels of expression at the plasma membrane. Channel activation was assessed from changes in calcium influx (fura-2 fluorescence measurements) or whole cell currents (patch clamp analysis). At room temperature (22–24 °C), exposure of TRPV4-transfected cells to hypotonic medium (225 mOsm/liter) or a non-protein kinase C (PKC)-activating phorbol ester derivative, 4α-phorbol 12,13-decanoate (100 nm), induces modest channel activation, whereas phorbol 12-myristate 13-acetate (100 nm), a PKC-activating phorbol ester, and shear stress (3–20 dyne/cm2) had minimal or no effect on channel activation. In contrast, at elevated temperatures (37 °C) the channel was rapidly activated by all stimuli. Inhibition of PKC by calphostin C (50 nm) or staurosporine (500 nm) abolished phorbol 12-myristate 13-acetate-induced activation of the channel without affecting the response to other stimuli. Ruthenium red (1 μm) effectively blocked the channel activity by all stimuli. It is concluded that temperature is a critical modulator of TRPV4 channel gating, leading to activation of the channel by a diverse range of microenvironmental chemical and physical signals utilizing a least two transduction pathways, one PKC-dependent and one PKC-independent. The convergence of multiple signals and transduction pathways on the same channel indicate that the channel functions as a molecular integrator of microenvironmental chemical and physical signals. The TRP calcium-permeable cation channels are a rapidly growing superfamily of channels expressed in a broad range of both excitable and nonexcitable cells. The channels, in general, are not voltage-activated but appear to be activated by a broad range of ligands and intracellular mediators (1Caterina M.J. Julius D. Annu. Rev. Neurosci. 2001; 24: 487-517Crossref PubMed Scopus (1333) Google Scholar, 2Clapham D.E. Runnels L.W. Strubing C. Nat. Rev. Neurosci. 2001; 2: 387-396Crossref PubMed Scopus (982) Google Scholar, 3Harteneck C. Plant T.D. Schultz G. Trends Neurosci. 2000; 23: 159-166Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 4Hoenderop J.G. Nilius B. Bindels R.J. Biochim. Biophys. Acta. 2002; 1600: 6-11Crossref PubMed Scopus (68) Google Scholar, 5Minke B. Cook B. Physiol. Rev. 2002; 82: 429-472Crossref PubMed Scopus (541) Google Scholar, 6Montell C. Birnbaumer L. Flockerzi V. Cell. 2002; 108: 595-598Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar, 7Vennekens R. Voets T. Bindels R.J. Droogmans G. Nilius B. Cell Calcium. 2002; 31: 253-264Crossref PubMed Scopus (162) Google Scholar). The superfamily has been divided into three main subfamilies based on structural and functional similarities: TPRVC, the canonical TRP channels first identified in Drosophila; TRPV, the vanilloid subfamily named after its first member, the vanilloid receptor (or capsaicin receptor; renamed TRPV1); and TRPM, the melatonin subfamily named after its first member, melatonin (see Refs. 1Caterina M.J. Julius D. Annu. Rev. Neurosci. 2001; 24: 487-517Crossref PubMed Scopus (1333) Google Scholar and 8Montell C. Birnbaumer L. Flockerzi V. Bindels R.J. Bruford E.A. Caterina M.J. Clapham D. Harteneck C. Heller S. Julius D. Kojima I. Mori Y. Penner R. Prawitt D. Scharenberg A.M. Schultz G. Shimizu S. Zhu M.X. Mol. Cell. 2002; 9: 229-231Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar for nomenclature). The TRPV subfamily has demonstrated a notable broad sensitivity to chemical and physical stimuli, particularly for TRPV1, which is activated by various noxious mediators, including heat, acid, and capsaicin (the hot ingredient of peppers), and by endogenous lipid mediators, such as diacylglycerol and anandamide (2Clapham D.E. Runnels L.W. Strubing C. Nat. Rev. Neurosci. 2001; 2: 387-396Crossref PubMed Scopus (982) Google Scholar, 5Minke B. Cook B. Physiol. Rev. 2002; 82: 429-472Crossref PubMed Scopus (541) Google Scholar, 9Gunthorpe M.J. Benham C.D. Randall A. Davis J.B. Trends Pharmacol. Sci. 2002; 23: 183-191Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar). Other members of the TRPV subfamily have been shown, so far, to have a narrower range of sensitivities: heat and insulin-like growth factor-I for TRPV2 (10Caterina M.J. Rosen T.A. Tominaga M. Brake A.J. Julius D. Nature. 1999; 398: 436-441Crossref PubMed Scopus (1292) Google Scholar, 11Kanzaki M. Zhang Y.-Q. 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The of the was to temperature a critical in the sensitivity of the TRPV4 channel to microenvironmental chemical and physical or stimuli. The TRPV4 channel was cloned from mouse M-1 kidney cells and expressed in expression of the temperature from to was to a critical sensitivity to channel for chemical and physical stimuli, a of signals. at the channel was to be to as by and to stress In the channel was to be to phorbol ester but two transduction pathways, a PKC-dependent and a of the channel by red but not by or of have been in L. Scholar). of the TRPV4 TRPV4 cDNA was and for from from mouse M-1 cells The cDNA was into the and with a V5 epitope on the C-terminal of the TRPV4 cDNA the expression to the The was into cells chemical to and the was the The was by with by to the TRPV4 cDNA and The was to that R. Harteneck C. Schultz G. Plant T. Nat. Cell Biol. 2000; 2: PubMed Scopus Google Scholar, M. M. Flockerzi V. 2000; PubMed Scopus Google Scholar). Cell and TRPV4 293 cells and Chinese hamster ovary cells 293 cells in medium at and cells in medium at The was transfected into 293 cells and cells the both a cDNA with the V5 and without to the and for of the 293 cells and cells transfected based on of the of cells the V5 epitope (see and the stably transfected cells by of transfected cells with The transfected cell based on the expression of the V5 epitope and functional of cells calcium to channel hypotonic medium and as by Y. A.M. A. A.J. Heller S. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar and H. Davis J.B. D. Jerman J.C. G.D. Hayes P. Flockerzi V. Droogmans G. Benham C.D. Nilius B. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google of TRPV4 activation, channel to the channel hypotonic medium or demonstrated cells the and of expressed TRPV4 with the C-terminal V5 epitope was assessed to the cells on with in for blocked with and with in for with medium was the was on a and the cells on a and of TRPV4 of cell was as Zhang PubMed Scopus Google of the C-terminal V5 by and activated the blocked with for with The to was in for with and on of intracellular calcium levels in cells the fluorescence as L. Physiol. Google Scholar, Cell Calcium. 2001; PubMed Scopus Google Scholar). and cells on with by of the cells with ester in medium for at The cells with medium and and to of in cells. The with cells, to the of a or a shear stress (see as and the was to the of The temperatures by of or by of The cells in or hypotonic medium as (see and cells on a and the for calcium was from the fluorescence by at and and the of the at in the The fluorescence to intracellular calcium activity as by G. M. Biol. Full Text PDF PubMed Scopus Google Scholar). is the at and is the of the fluorescence at in and is the of is the in of and and is the in the of the of the of shear stress on TRPV4 channel activation, the cells on to the of a and the was to the of the as or the was by a to shear from to intracellular calcium levels in cells and the for clamp in whole cell was for of whole cell currents clamp to a as Physiol. Google Scholar). with a and had of (see and The was a into a from the was by The temperature of the (see and was at a to the as the all was at a of of at with a as by H. Davis J.B. D. Jerman J.C. G.D. Hayes P. Flockerzi V. Droogmans G. Benham C.D. Nilius B. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The was by a to for by a from to of and to the of and 293 or cells and in for all functional intracellular calcium in or as The of The was the was to the to whole cell the medium was and The was and a PKC-activating phorbol ester, and a phorbol ester, at (100 in and a channel was at of in The in medium and C a of and staurosporine a broad PKC at of in and (1 in other from calcium levels in cells for on a and the to a for is the of of was from a The are as the The with or as was to be of of the TRPV4 in 293 cells and cells was with the and in TRPV4-transfected cells and TRPV4 expression was the cells. The channel was to be expressed in the of both the 293 and cells, expression in the and and in the plasma membrane. in the of expression the V5 epitope construct in the of at the plasma membrane. In the of and of the was not or expression of the The of expression is with the by a TRPV4 construct was utilizing a to the C as a R. Harteneck C. Schultz G. Plant T. Nat. Cell Biol. 2000; 2: PubMed Scopus Google Scholar, M. M. Flockerzi V. 2000; PubMed Scopus Google Scholar). The TRPV4 was by of the V5 epitope construct and the for in and a was in both transfected 293 and cells, whereas no in cells. The molecular of the in both transfected 293 and cells was to be construct the C-terminal the V5 epitope and the TRPV4 on is of on functional of the TRPV4 channel assessed from changes in intracellular calcium channel activation. of levels in cells the was in the expression of the TRPV4 construct with the V5 epitope not a fluorescence and not with the (or in to that for the Cell Calcium. Scholar). on the effect of the temperature from room temperature (22–24 °C) to without the of channel in at room temperature levels in and TRPV4-transfected cells and for and transfected 293 cells, and and for and transfected cells, At levels elevated for both and transfected cells, and for and transfected 293 cells, and and for and transfected cells, the of the cells at two not appear to in a in the was In all the effect of temperature on TRPV4 activation was in 293 cells, with a in cells. of TRPV4 by has been that phorbol ester such as and TRPV4 by a H. Davis J.B. D. Jerman J.C. G.D. Hayes P. Flockerzi V. Droogmans G. Benham C.D. Nilius B. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). at room effect of elevated temperature on the lipid signals TRPV4 in is a of PKC at of or whereas the of are PKC-independent. the of temperature on the of both and at In at room temperature in transfected 293 cells, the of (100 nm) a modest in in to a of A and At the of a response with to a of At elevated temperatures the response to a of the response at room response of was in 293 cells not The response to (100 nm) was At room the of in transfected 293 cells a minimal with to C and In contrast, at a response with to a of the effect of from no response at room temperature to a response at elevated of TRPV4 by stress in the of hypotonic is a of the TRPV4 It was in the that cells to hypotonic at room a modest in was in transfected 293 cells, from to and cells at hypotonic a with from to changes not in cells not the of physical stress on TRPV4 gating, the to the of shear to changes in on channel activation. At room temperature in transfected 293 cells, the shear stress from to had or no effect on and a with a of response to at room temperature as by R. Harteneck C. Schultz G. Plant T. Nat. Cell Biol. 2000; 2: PubMed Scopus Google Scholar). In contrast, at shear stress to in a in to a of resulting in (see in At the channel response was by the of shear stress in shear stress from to or in in with a that elevated temperatures are to TRPV4 channel activation to shear with a or on of a channel PKC-dependent and TRPV4 TRP channels are activated by of calcium from not appear to be the for TRPV4 activation by physical and chemical stimuli. At of calcium from the medium abolished the of or of calcium abolished in exposure to and of the appear to the of calcium from the calcium the transduction pathways of TRPV4 not appear to signals or of calcium from transduction pathways that TRPV4 activation, a of PKC was at the of a phorbol ester, a response in a in of A and to that cells first with C (50 nm), a of the of was not with the in of A and is as not is a of particularly at the modest levels of in the its be a PKC-dependent the of a response in with a in of C and PKC first by of C (50 nm), the of on with the C and PKC by the of staurosporine (50 or nm), a broad PKC of the effect of on was with changes and with and the of are abolished by PKC The of of hypotonic on TRPV4 activation is not a for PKC in the of of PKC by C (50 nm) on the response to evaluated. in and C had or no effect on the The of on TRPV4 appear to be transduction pathways not to of the channels activated by the physical and chemical in the channel for of the of calcium-permeable channels, such as and to not leading to calcium influx as by for TRPV4 Y. A.M. A. A.J. Heller S. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). has been to TRPV4 channels R. Harteneck C. Schultz G. Plant T. Nat. Cell Biol. 2000; 2: PubMed Scopus Google Scholar, H. Davis J.B. D. Jerman J.C. G.D. Hayes P. Flockerzi V. Droogmans G. Benham C.D. Nilius B. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Shimizu I. Tominaga M. Caterina M. Neurosci. 2002; PubMed Google Scholar). was to be of TRPV4 in the μm) and a to the channels activated by of the stimuli. The of with effectively the by the in the of to activation of the channel abolished channel by for with and shear stress not after channel activation, its the effect not appear to be as to a of calcium for all physical and chemical stimuli. the of (1 μm) was to the in for and shear stress by and had a for all physical and chemical as all activated the same TRPV4 of TRPV4 that the of on intracellular calcium levels at to activation of TRPV4 channels, as for and by (12Peier A.M. Reeve A.J. Andersson D.A. Moqrich A. Earley T.J. Hergarden A.C. Story G.M. Colley S. Hogenesch J.B. McIntyre P. Bevan S. Patapoutian A. Science. 2002; 296: 2046-2049Crossref PubMed Scopus (757) Google Scholar, Y. A.M. A. A.J. Heller S. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, H. Davis J.B. D. Jerman J.C. G.D. Hayes P. Flockerzi V. Droogmans G. Benham C.D. Nilius B. 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Biol. 2002; Full Text Full Text PDF PubMed Scopus (541) Google the diverse of the It be that of temperature temperature of the channel not A of of activation of the TRPV4 channel the that elevated temperatures the of the channel to a diverse range of is that multiple or pathways of the channel to the of signals. hypotonic and shear stress both channel gating, the channel has both and The by which physical signals the physical signals on the same channel that the channel is a of The that phorbol ester the channel both PKC-dependent and transduction pathways A and the that the channel be by multiple endogenous such as the transduction pathways that in Y. 2001; PubMed Scopus Google Scholar). The of a transduction phorbol in a is but such pathways are is that have that phorbol in and critical in functions M.J. P. T. Reilly M. H. Pharmacol. 2000; PubMed Scopus Google Scholar). of such calcium and channels has been in T. Physiol. Google Scholar, T. Y. T. S. M. 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