TRPC1-mediated Inhibition of 1-Methyl-4-phenylpyridinium Ion Neurotoxicity in Human SH-SY5Y Neuroblastoma Cells

Mammalian homologues of the Drosophila canonical transient receptor potential (TRP) proteins have been implicated to function as plasma membrane Ca2+ channels. This study examined the role of TRPC1 in human neuroblastoma (SH-SY5Y) cells. SH-SY5Y cells treated with an exogenous neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+) significantly decreased TRPC1 protein levels. Confocal microscopy on SH-SY5Y cells treatment with MPP+ showed decreased plasma membrane staining of TRPC1. Importantly, overexpression of TRPC1 reduced neurotoxicity induced by MPP+. MPP+-induced α-synuclein expression was also suppressed by TRPC1 overexpression. Protection of SH-SY5Y cells against MPP+ was significantly decreased upon the overexpression of antisense TRPC1 cDNA construct or the addition of a nonspecific transient receptor potential channel blocker lanthanum. Activation of TRPC1 by thapsigargin or carbachol decreased MPP+ neurotoxicity, which was partially dependent on external Ca2+. Staining of SH-SY5Y cells with an apoptotic marker (YO-PRO-1) showed that TRPC1 protects SH-SY5Y neuronal cells against apoptosis. Further, TRPC1 overexpression inhibited cytochrome c release and decreased Bax and Apaf-1 protein levels. Interpretation of the above data suggests that reduction in the cell surface expression of TRPC1 following MPP+ treatment may be involved in dopaminergic neurodegeneration. Furthermore, TRPC1 may inhibit degenerative apoptotic signaling to provide neuroprotection against Parkinson's disease-inducing agents. Mammalian homologues of the Drosophila canonical transient receptor potential (TRP) proteins have been implicated to function as plasma membrane Ca2+ channels. This study examined the role of TRPC1 in human neuroblastoma (SH-SY5Y) cells. SH-SY5Y cells treated with an exogenous neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+) significantly decreased TRPC1 protein levels. Confocal microscopy on SH-SY5Y cells treatment with MPP+ showed decreased plasma membrane staining of TRPC1. Importantly, overexpression of TRPC1 reduced neurotoxicity induced by MPP+. MPP+-induced α-synuclein expression was also suppressed by TRPC1 overexpression. Protection of SH-SY5Y cells against MPP+ was significantly decreased upon the overexpression of antisense TRPC1 cDNA construct or the addition of a nonspecific transient receptor potential channel blocker lanthanum. Activation of TRPC1 by thapsigargin or carbachol decreased MPP+ neurotoxicity, which was partially dependent on external Ca2+. Staining of SH-SY5Y cells with an apoptotic marker (YO-PRO-1) showed that TRPC1 protects SH-SY5Y neuronal cells against apoptosis. Further, TRPC1 overexpression inhibited cytochrome c release and decreased Bax and Apaf-1 protein levels. Interpretation of the above data suggests that reduction in the cell surface expression of TRPC1 following MPP+ treatment may be involved in dopaminergic neurodegeneration. Furthermore, TRPC1 may inhibit degenerative apoptotic signaling to provide neuroprotection against Parkinson's disease-inducing agents. Parkinson's disease is a progressive neurodegenerative disorder associated with selective loss of the dopaminergic neurons in the substantia nigra pars compacta (1Hirsch E.C. Hoglinger G. Rousselet E. Breidert T. Parain K. Feger J. Ruberg M. Prigent A. Cohen-Salmon C. Launay J.M. J. Neural Transm. 2003; 3: 89-100Google Scholar). Neurotoxins, such as 1-methyl-4-phenylpyridinium ion (MPP+), 1The abbreviations used are: MPP+, 1-methyl-4-phenylpyridinium ion; ER, endoplasmic reticulum; 2APB, 2-aminoethoxydiphenyl borate; RT, reverse transcription; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; TRP, transient receptor potential; SERCA, sarco-endoplasmic reticulum Ca2+ ATPase pump; AMPA, α-amino-5-methyl-3-hydroxy-4-isoxazolepropionic acid; BAPTA, 2-bis(O-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra (acetoxymethyl ester). cause selective nigral dopaminergic lesions and cause Parkinsonian syndrome (2Sandler M. Carter S.B. Hunter K.R. Stern G.M. Nature. 1973; 241: 439-443Crossref PubMed Scopus (314) Google Scholar, 3Ballard P.A. Tetrud J.W. Langston J.W. Neurology. 1985; 35: 949-956Crossref PubMed Google Scholar, 4Moser A. Kompf D. Life Sci. 1992; 50: 1885-1891Crossref PubMed Scopus (76) Google Scholar, 5Meissner W. Prunier C. Guilloteau D. Chalon S. Gross C.E. Bezard E. Mol. Neurobiol. 2003; 28: 209-218Crossref PubMed Scopus (71) Google Scholar). Although the underlying cause of dopaminergic cell death or the molecular mechanism by which these cells degenerate is still not fully understood, several molecular mechanisms have been proposed to play a role that includes overproduction of reactive oxygen species, impairment of mitochondrial respiration, disturbances of Ca2+ homeostasis, and excitotoxicity (6Beal M.F. Ann. Neurol. 1995; 38: 357-366Crossref PubMed Scopus (1264) Google Scholar, 7Fahn S. Cohen G. Ann. Neurol. 1992; 32: 804-812Crossref PubMed Scopus (866) Google Scholar, 8Tatton W.G. Olanow C.W. Biochim. Biophys. Acta. 1999; 1410: 195-213Crossref PubMed Scopus (250) Google Scholar, 9Sheehan J.P. Swerdlow R.H. Parker W.D. Miller S.W. Davis R.E. Tuttle J.B. J. Neurochem. 1997; 68: 1221-1233Crossref PubMed Scopus (139) Google Scholar, 10Doble A. Pharmacol. Ther. 1999; 81: 163-221Crossref PubMed Scopus (643) Google Scholar). Of these, Ca2+ homeostasis is believed to play an important role, because Ca2+ has both stimulatory and inhibitory roles in the cell death process. Release of Ca2+ from the endoplasmic reticulum (ER) followed by Ca2+ influx from the extracellular environment induces oxidative stress, which could activate cell death cascades (11Ermak G. Davies K.J. Mol. Immunol. 2002; 38: 713-721Crossref PubMed Scopus (666) Google Scholar). Ca2+ concentration is very tightly regulated in neuronal cells. Disturbances in neuronal Ca2+ homeostasis have been implicated in a variety of neuropathological conditions (12Lehotsky J. Kaplan P. Babusikova E. Strapkova A. Murin R. Physiol. Res. 2003; 52: 269-274PubMed Google Scholar). Hypotheses about how such disturbances might cause neurodegeneration have largely focused on excessive concentration of cytosolic Ca2+ (Ca2+i), which could cause overactivation of a variety of potentially destructive processes (11Ermak G. Davies K.J. Mol. Immunol. 2002; 38: 713-721Crossref PubMed Scopus (666) Google Scholar). More recently, several lines of evidence suggests that neuronal toxicity is not simply a function of increased Ca2+i. For example, treatments with AMPA or KCl can increase Ca2+i up to 1–2 μm in cortical neurons, without causing toxicity (13Chen Q. Surmeier D.J. Reiner A. Exp. Neurol. 1999; 159: 283-296Crossref PubMed Scopus (35) Google Scholar), whereas equally high Ca2+ loads are toxic when entering via the N-methyl-d-aspartate channels but not when entering via the voltage-dependent Ca2+ channels (13Chen Q. Surmeier D.J. Reiner A. Exp. Neurol. 1999; 159: 283-296Crossref PubMed Scopus (35) Google Scholar), suggesting that the source of increased Ca2+i or the calcium channel itself is critical for neuronal cell death. Further, in some neurons decreasing Ca2+i is toxic, whereas in others a modest increase in Ca2+i can be neuroprotective, indicating a “set point” mechanism for the effect of Ca2+i (11Ermak G. Davies K.J. Mol. Immunol. 2002; 38: 713-721Crossref PubMed Scopus (666) Google Scholar, 13Chen Q. Surmeier D.J. Reiner A. Exp. Neurol. 1999; 159: 283-296Crossref PubMed Scopus (35) Google Scholar). The action of Ca2+ ion is mediated by several mechanisms, which are highlighted by the central role of Ca2+ in apoptotic processes and neuronal excitotoxicity. Mitochondria not only functions as an ATP producer but also functions as a regulator of intracellular Ca2+ homeostasis. Increased mitochondrial Ca2+ overload as a result of excitotoxicity has been associated with the generation of superoxide and may induce the release of proapoptotic mitochondrial proteins, proceeding through DNA fragmentation/condensation and culminating in cell demise by apoptosis (14Anglade P. Vyas S. Javoy-Agid F. Herrero M.T. Michel P.P. Marquez J. Mouatt-Prigent A. Ruberg M. Hirsch E.C. Agid Y. Histol. Histopathol. 1997; 12: 25-31PubMed Google Scholar, 15Mochizuki H. Goto K. Mori H. Mizuno Y. J. Neurol. 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The addition of thapsigargin a release of Ca2+ from the which could activate plasma membrane Ca2+ channels as Ca2+ channels. Mammalian homologues of the transient receptor potential have been as the plasma membrane Ca2+ influx channels Physiol. 2002; PubMed Scopus Google Scholar, C. Sci. Scholar, J.W. Full Text Full Text PDF PubMed Scopus Google Scholar, W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of the has been that are and C. Sci. Scholar, M.M. H. Neurobiol. PubMed Scopus Google Scholar). are channels for which T. T. C. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), and are to be by and of channels not only function as Ca2+ influx channels but are also involved in cell and as functions M.M. H. Neurobiol. PubMed Scopus Google Scholar). overexpression and has that and associated with Ca2+ channels and could be by the expression of these proteins is very TRPC1 is the only is and is in the plasma membrane W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar, M.M. H. Neurobiol. PubMed Scopus Google Scholar, T. T. C. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, K. 2002; PubMed Scopus Google Scholar). of proteins to the plasma membrane is for which is dependent on to with TRPC1 with and with a protein is critical for to the plasma membrane M. A. H. J. PubMed Scopus Google Scholar, W. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Further, and have been to be in and are to the membrane upon S. C. S. Mol. Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. PubMed Scopus Google Scholar). that TRPC1 functions as Ca2+ influx channel W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar, C. T. D. J. Scopus Google Scholar). The study was to the of MPP+ on the of TRPC1 in human dopaminergic SH-SY5Y cells. data that expression of TRPC1 is significantly reduced in cells treated with MPP+. Further, overexpression of the TRPC1 dopaminergic neurons from toxicity by MPP+, and of TRPC1 reduced TRPC1 protein and an increased cell death. that critical proapoptotic are inhibited in cells treated with MPP+. data an important role of TRPC1 in the of dopaminergic neurons against Parkinson's disease-inducing agents. SH-SY5Y and neuroblastoma cells from the in a with and and with and was SH-SY5Y cells in and and in the as MPP+ was to and was the of the for to the of the toxic SH-SY5Y cells or TRPC1 antisense cDNA or as W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar, C. T. D. J. Scopus Google Scholar). ion (MPP+) and from and from 2-aminoethoxydiphenyl was from of the and was from SH-SY5Y cells and was treated with a concentration of of of in a KCl for The was by a concentration of and for The used for and are in cDNA and as W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar). of the was on a and by or of the in a cells on a of The for followed by addition of MPP+. was by as S. E.C. M. J. Res. PubMed Scopus Google Scholar). for with the of in μm was to and in a for The was from and the was for The was with of in and the was in a and and cells and as W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar, C. T. D. J. Scopus Google Scholar). The cells and from cell J. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar). as by and D. M. Res. PubMed Scopus Google Scholar). concentration was by the protein of the proteins on to and with of the was used to for and For α-synuclein of the cell on a and with α-synuclein used to the The proteins on the membrane and Confocal SH-SY5Y cells on with and for The cells and for For TRPC1 the cells treated with for The cells with and with W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. S. Mol. Full Text Full Text PDF PubMed Scopus Google Scholar). Confocal a with a Staining apoptosis was used to apoptosis as the This apoptotic and cells by and (YO-PRO-1) The cells a a The and cells whereas apoptotic cells have a The apoptotic and cells and the of cells TRPC1 in SH-SY5Y the expression of proteins, was of from SH-SY5Y cells was used for cDNA for of the showed that and in SH-SY5Y whereas expression of and was not conditions The of expression of and was not to or because the when DNA was used as not in a a and a of Although these these which the of and not are also was and of that and in SH-SY5Y cells of the that was followed by and of was also in only and in SH-SY5Y whereas and not in The with the and and the is an of of in SH-SY5Y cells that these channels could have an important role in the of the dopaminergic neuronal cells. of MPP+ on TRPC1 the role of MPP+, SH-SY5Y cells with μm of MPP+, and TRPC1 protein in in the TRPC1 protein when with MPP+ for an of with MPP+ showed a in the TRPC1 levels. on these that of the TRPC1 protein was reduced of with MPP+, which the of with showed in protein also or in protein was of with MPP+ not these that the in the TRPC1 protein upon MPP+ treatment is and could be the effect of the MPP+ TRPC1 study the role of MPP+ on the of the TRPC1 microscopy was of the TRPC1 protein a plasma membrane staining with some membrane staining of SH-SY5Y cells without the TRPC1 showed staining not are with TRPC1 protein was in the plasma membrane W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar, W. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). MPP+ treatment for on SH-SY5Y cells showed a in the plasma membrane staining of TRPC1 also upon of with MPP+ TRPC1 was in the in the plasma membrane not Confocal with cells TRPC1 and treated with MPP+ showed a plasma membrane staining to that of the cells. a of staining was for cells TRPC1 expression was antisense construct and treated with MPP+ for Further, with TRPC1 protein significantly reduced in cells antisense construct W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar). that MPP+ treatment not only TRPC1 protein but also and overexpression of TRPC1 effect by to the of TRPC1 SH-SY5Y from the role of TRPC1 in SH-SY5Y TRPC1 of of for was used to SH-SY5Y have used to TRPC1 protein in human cells C. T. D. J. Scopus Google Scholar). in on from and TRPC1 protein was treated for with MPP+ a in TRPC1 protein levels. This in TRPC1 protein was as in MPP+ treatment on SH-SY5Y cells TRPC1 of of showed a increase in the of the TRPC1 protein SH-SY5Y cells with a of of of showed increase in the TRPC1 protein upon of MPP+ treatment not with which showed in protein MPP+ is a toxic of by and neurodegeneration. to TRPC1 has a role in the of dopaminergic SH-SY5Y neuronal SH-SY5Y cells on a and treated with the both in and in TRPC1 cells. SH-SY5Y cells treated with MPP+ showed a in the cell reduction in cells as with SH-SY5Y cells TRPC1 showed a increase in cell cell The of Parkinson's disease are the loss of neuronal and the of and are intracellular of several proteins are a of proteins and are to be in Parkinson's disease and also in cells to MPP+ treatment (2Sandler M. Carter S.B. Hunter K.R. Stern G.M. Nature. 1973; 241: 439-443Crossref PubMed Scopus (314) Google Scholar, 5Meissner W. Prunier C. Guilloteau D. Chalon S. Gross C.E. Bezard E. Mol. Neurobiol. 2003; 28: 209-218Crossref PubMed Scopus (71) Google Scholar, S. E.C. M. J. Res. PubMed Scopus Google Scholar). to TRPC1 has a role in the of cell from and TRPC1 cells both in the and in the of Parkinson's disease-inducing in cells treated with MPP+ showed of SH-SY5Y cells TRPC1 a in α-synuclein protein upon MPP+ treatment increased of α-synuclein was when TRPC1 was antisense construct Further, these conditions showed effect on the expression of these a role for TRPC1 in the expression of α-synuclein and Activation of TRPC1 in SH-SY5Y the role of TRPC1 in the of SH-SY5Y SH-SY5Y cells with antisense and SH-SY5Y cells antisense cDNA showed a in the of SH-SY5Y cells treated with MPP+. Importantly, was significantly cells treated with MPP+ a as with in Activation of TRPC1 carbachol significantly increased the of SH-SY5Y cells from MPP+. in the of external Ca2+ showed against toxicity Activation of TRPC1 with blocker thapsigargin also showed increased cell and was partially dependent on external Ca2+ increased cell was dependent on the of of Ca2+ because in the of Ca2+ was of TRPC1 cells with intracellular Ca2+ increased cell of cells with significantly decreased cell Although the addition of an showed a in the by TRPC1 was not these that of TRPC1 is critical for the of dopaminergic neurons, which is partially dependent on the Ca2+ influx of TRPC1. of the TRPC1 SH-SY5Y via of the neuronal death by apoptosis and partially via to the role of TRPC1 in the of SH-SY5Y neurons, examined effect both on apoptosis and on cell death was whereas to the cell death from apoptosis an apoptotic marker was in SH-SY5Y cells without treatment showed cell death data are in cells treated with MPP+ showed a increase in cell death via the apoptotic as by is as an which cell death upon MPP+ cell death via the was to that of SH-SY5Y cells without MPP+ treatment are to that MPP+ cell death via the apoptotic Physiol. 2002; PubMed Scopus Google Scholar, C. Sci. Scholar, J.W. Full Text Full Text PDF PubMed Scopus Google Scholar). SH-SY5Y cells TRPC1 showed a in the cell death via apoptosis in cells of whereas was in cell death via data are in apoptotic cell death was when TRPC1 expression was antisense construct in cells of as in the above that TRPC1 protects SH-SY5Y neuronal cells via mediated cell death. of TRPC1 the of for in SH-SY5Y the function of proteins for the mediated cell death process. with above TRPC1 proteins for the of the apoptotic has been that the expression intracellular of the proapoptotic protein Bax is critical for mediated cell death. Bax and death proteins result in Bax membrane and of the mitochondrial which cytochrome the cytochrome c with proteins the of which the and that are of apoptosis. to that TRPC1 has a role in mediated cell from of cells and the of cytochrome c and Bax proteins in in cytochrome c protein was in the membrane of SH-SY5Y cells. treatment with MPP+ decreased cytochrome c protein in the mitochondrial membrane of SH-SY5Y cells SH-SY5Y cells TRPC1 protein showed a increase in the cytochrome c treated with MPP+ whereas of TRPC1 decreased cytochrome c not that the release of cytochrome c is inhibited in cells TRPC1. Bax showed that Bax protein increased in SH-SY5Y cells treated with MPP+. This increase in Bax protein was significantly reduced in cells TRPC1 Further, in the protein was in protein with on membrane apoptotic neuronal cytochrome c is of to Apaf-1 This in of apoptotic neuronal death. Apaf-1 proteins in of cells. TRPC1 overexpression significantly decreased the of Apaf-1 protein in suggesting that TRPC1 protects SH-SY5Y neurons by the proapoptotic has been that cytosolic Ca2+ induced of Apaf-1 in human SH-SY5Y neuroblastoma cells C. D. S. M. J. Neurochem. PubMed Scopus Google Scholar). the data in and that TRPC1 protects SH-SY5Y cells by proteins important for apoptotic process. have that MPP+, an exogenous involved in the of dopaminergic neurons, also inhibited TRPC1 proteins are a plasma membrane Ca2+ which are in cell that MPP+ significantly TRPC1 protein levels. This in the TRPC1 protein was not a because the expression of the calcium protein was not Ca2+ channels are critical for the of neuronal of these channels might the of several Parkinson's TRPC1 protein is to be in the plasma functions as a Ca2+ channel W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Confocal microscopy staining in the plasma membrane of cells that was in cells. MPP+ not only TRPC1 protein but also Further, the addition of MPP+ significantly reduced thapsigargin and Ca2+ influx not This in Ca2+ influx could be to the of TRPC1 in the plasma the not upon MPP+ treatment not which in the of the calcium was TRPC1 SH-SY5Y against MPP+-induced is a of and is to induce cell death in dopaminergic neurons (1Hirsch E.C. Hoglinger G. Rousselet E. Breidert T. Parain K. Feger J. Ruberg M. Prigent A. Cohen-Salmon C. Launay J.M. J. Neural Transm. 2003; 3: 89-100Google Scholar, 3Ballard P.A. Tetrud J.W. Langston J.W. Neurology. 1985; 35: 949-956Crossref PubMed Google Scholar). the role of SH-SY5Y cells with antisense TRPC1 or TRPC1 with overexpression of TRPC1 showed a increase in the TRPC1 protein and antisense significantly decreased TRPC1 W. T. J. R. J. Full Text Full Text PDF PubMed Scopus Google Scholar). TRPC1 overexpression not only TRPC1 protein in the plasma membrane but also cell whereas cells antisense TRPC1 showed a in the cell that was significantly cells treated with MPP+. in the TRPC1 upon MPP+ treatment to a reduced Ca2+ which could to cell death. lines of evidence the effect of Ca2+ a in Ca2+ was for human T. Mori Y. J. Pharmacol. PubMed Scopus Google Scholar). Although that TRPC1 is decreased upon MPP+ SH-SY5Y neuroblastoma cell showed that from TRPC1 are also in these cells. of proteins could still the function of SH-SY5Y cells because is the only channel that is by T. T. C. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), and is to proteins are also upon MPP+ of TRPC1 is for role, TRPC1 both in the and in the of Ca2+. that of the TRPC1 protein by thapsigargin or carbachol showed an increased of dopaminergic SH-SY5Y Ca2+ via the TRPC1 channel protein was not for the of MPP+-induced cell death. Ca2+ play a role in of intracellular Ca2+ by the of external Ca2+ showed in the of Ca2+. Activation of TRPC1 could itself to the plasma membrane or with mechanism has been in and an increased plasma membrane staining was upon S. C. S. Mol. Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. PubMed Scopus Google Scholar). of TRPC1 channels significantly decreased the addition of 2APB, a nonspecific channel showed of SH-SY5Y cells against MPP+, also in the role of TRPC1 was in the of are with the addition of in C. G. J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). these on could function Further, not only Ca2+ channels T. T. S. T. K. J. 1997; PubMed Scopus Google but also proteins, such as the sarco-endoplasmic reticulum Ca2+ ATPase R.E. F. J. 2002; PubMed Scopus Google Scholar), the voltage-dependent channels Y. M. R. 2002; 32: PubMed Scopus Google Scholar), J.P. E.J. J. 2003; PubMed Scopus Google Scholar), and channels Q. C. J. M. J. 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PubMed Scopus Google was not in the decreased Bax in cytochrome c and of apoptotic cell death to the that mitochondrial may be Bax is believed to action the mitochondrial membrane by decreasing the mitochondrial potential and of cytochrome c the to and cell death 1999; PubMed Scopus Google Scholar). of mitochondrial Ca2+ is to be by release of cytochrome indicating an increase in of both the and mitochondrial Q. C. J. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar). that is a cytochrome c from and the receptor on the apoptosis S. K. 2003; PubMed Scopus Google Scholar). that TRPC1 may be an important channel in these and in protein may cell the that MPP+ treatment plasma membrane staining of TRPC1. Further, overexpression of TRPC1 showed an increased of dopaminergic SH-SY5Y of Ca2+ that TRPC1 protects SH-SY5Y neurons by the of the proteins for mediated cell death. to be TRPC1 the of the proteins for apoptotic cell death. have used the SH-SY5Y cell which is a from the human neuroblastoma cell which and C.W. Exp. Neurol. PubMed Scopus Google Scholar). SH-SY5Y to dopaminergic neurons in could be source of cell lines in the role of TRPC1 in the neuroprotection of dopaminergic neurons as as in the intracellular signaling mechanisms that are for these and the the loss of TRPC1 protein and mitochondrial and for and of the also for with