Development - PACAP signaling in neural cells

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PACAP signaling in neural cells

PACAP is a member of the secretin superfamily of neuropeptides expressed in both the brain and peripheral nervous system. PACAP acts via specific PACAP receptor 1 to promote neurotrophic and neurodevelopmental effects on neural cells [1], [2], [3].

PACAP receptor 1 belongs to the family of G-protein-coupled receptors. It acts via G-protein alpha-s to activate Adenylate cyclase type I [4], [5], and via G-protein alpha-q/11 to activate PLC-beta [6], [7], [8], [9], [10].

Activation of Adenylate cyclase type I by PACAP signaling leads to enhanced Cyclic AMP production and activation of PKA-reg (cAMP-dependent)/ PKA-cat (cAMP-dependent). PKA-cat (cAMP-dependent) activates RAP-1A [2], [3], [11]. PACAP also activates RAP-1A in a PKA-independent manner via Cyclic AMP-mediated activation of cAMP-GEFI and cAMP-GEFII [3], [12], [13]. RAP-1A triggers B-Raf)/ MEK1(MAP2K1), MEK2(MAP2K2)/ ERK1/2 cascade that leads to phosphorylation of two proteins, Elk-1) and CREB1. p90RSK2(RPS6KA3) most likely phosphorylates CREB1 [14], [15]) [5], [11], [16]. CREB1 coupled to ATF-1 induces expression of the TY3H [2], [17]. Activation of Elk-1 and CREB1 by PACAP signaling stimulates neurite outgrowth (see neuron projection development) and promotes cell differentiation of PC12, granule cells, and neural stem cells [2], [5], [18].

PACAP stimulation of PLC-beta activity leads to 1,2-Diacyglycerol and IP3 production and Ca('2+) release from internal stores [7], [8], [9]. These second messengers activate conventional forms of cPKC (conventional). cPKC (conventional) induces B-Raf/ MEK1(MAP2K1), MEK2(MAP2K2)/ ERK1/2 cascade, leading to activation of CREB1 and Elk-1 and stimulation of differentiation of the neural cells (see neurogenesis) [5], [19], [20], [21].

PACAP-mediated activation of CREB1 leads to enhanced expression of the c-Fos [1], [22], [23], [24], [25]. c-Fos induces Bcl-2 transcription [26]. Bcl-2 prevents Bax -mediated release of the Cytochrome c from mitochondria and suppresses activation of Caspase-3 [25]. In addition, PACAP-stimulated PKA-cat (cAMP-dependent) suppresses Caspase-3 activity probably via phosphorylation of Caspase-9 [25], [27], [28], [29], [30]. This leads to enhanced survival of neural cells (see anti-apoptosis [3], [28].



Objects list:

1,2-Diacyglycerol 1,2-Diacyglycerol Compound group
ATF-1 Cyclic AMP-dependent transcription factor ATF-1
Adenylate cyclase type I Adenylate cyclase type 1
B-Raf Serine/threonine-protein kinase B-raf
Bax Apoptosis regulator BAX
Bcl-2 Apoptosis regulator Bcl-2
CREB1 Cyclic AMP-responsive element-binding protein 1
Ca('2+) Chemical IUPAC name calcium(+2) cation
Caspase-3 Caspase-3
Caspase-9 Caspase-9
Cyclic AMP Chemical IUPAC name (1S,6R,8R,9R)-8-(6-amino-8-bromopurin-9-yl)-3-hydroxy-3-oxo-2,4,7-trioxa-35-phosphabicyclo[4.3.0]nonan-9-ol
Cytochrome c Cytochrome c
ERK1/2 Erk 1/2 Protein group
Elk-1 ETS domain-containing protein Elk-1
G-protein alpha-q/11 G-protein alpha-q/11 Protein group
G-protein alpha-s Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
IP3 Chemical IUPAC name [(1R,2S,3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-diphosphonooxycyclohexyl] dihydrogen phosphate
MEK1(MAP2K1) Dual specificity mitogen-activated protein kinase kinase 1
MEK2(MAP2K2) Dual specificity mitogen-activated protein kinase kinase 2
PACAP Pituitary adenylate cyclase-activating polypeptide
PACAP receptor 1 Pituitary adenylate cyclase-activating polypeptide type I receptor
PKA-cat (cAMP-dependent) Protein kinase, cAMP-dependent, catalytic Protein group
PKA-reg (cAMP-dependent) Cyclic AMP-dependent protein kinase A regulatory subunit Protein group
PLC-beta Phospholipase C, beta Protein group
RAP-1A Ras-related protein Rap-1A
TY3H Tyrosine 3-monooxygenase
c-Fos Proto-oncogene c-Fos
cAMP-GEFI Rap guanine nucleotide exchange factor 3
cAMP-GEFII Rap guanine nucleotide exchange factor 4
cPKC (conventional) conventional Protein kinase C Protein group
p90RSK2(RPS6KA3) Ribosomal protein S6 kinase alpha-3

References:

  1. Vaudry D, Gonzalez BJ, Basille M, Yon L, Fournier A, Vaudry H
    Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacological reviews 2000 Jun;52(2):269-324
  2. Vaudry D, Stork PJ, Lazarovici P, Eiden LE
    Signaling pathways for PC12 cell differentiation: making the right connections. Science (New York, N.Y.) 2002 May 31;296(5573):1648-9
  3. Botia B, Basille M, Allais A, Raoult E, Falluel-Morel A, Galas L, Jolivel V, Wurtz O, Komuro H, Fournier A, Vaudry H, Burel D, Gonzalez BJ, Vaudry D
    Neurotrophic effects of PACAP in the cerebellar cortex. Peptides 2007 Sep;28(9):1746-52
  4. Pisegna JR, Wank SA
    Cloning and characterization of the signal transduction of four splice variants of the human pituitary adenylate cyclase activating polypeptide receptor. Evidence for dual coupling to adenylate cyclase and phospholipase C. The Journal of biological chemistry 1996 Jul 19;271(29):17267-74
  5. Ravni A, Bourgault S, Lebon A, Chan P, Galas L, Fournier A, Vaudry H, Gonzalez B, Eiden LE, Vaudry D
    The neurotrophic effects of PACAP in PC12 cells: control by multiple transduction pathways. Journal of neurochemistry 2006 Jul;98(2):321-9
  6. Deutsch PJ, Sun Y
    The 38-amino acid form of pituitary adenylate cyclase-activating polypeptide stimulates dual signaling cascades in PC12 cells and promotes neurite outgrowth. The Journal of biological chemistry 1992 Mar 15;267(8):5108-13
  7. Hezareh M, Schlegel W, Rawlings SR
    PACAP and VIP stimulate Ca2+ oscillations in rat gonadotrophs through the PACAP/VIP type 1 receptor (PVR1) linked to a pertussis toxin-insensitive G-protein and the activation of phospholipase C-beta. Journal of neuroendocrinology 1996 May;8(5):367-74
  8. Van Rampelbergh J, Poloczek P, Françoys I, Delporte C, Winand J, Robberecht P, Waelbroeck M
    The pituitary adenylate cyclase activating polypeptide (PACAP I) and VIP (PACAP II VIP1) receptors stimulate inositol phosphate synthesis in transfected CHO cells through interaction with different G proteins. Biochimica et biophysica acta 1997 Jun 27;1357(2):249-55
  9. Zhou CJ, Yada T, Kohno D, Kikuyama S, Suzuki R, Mizushima H, Shioda S
    PACAP activates PKA, PKC and Ca(2+) signaling cascades in rat neuroepithelial cells. Peptides 2001 Jul;22(7):1111-7
  10. Macdonald DS, Weerapura M, Beazely MA, Martin L, Czerwinski W, Roder JC, Orser BA, MacDonald JF
    Modulation of NMDA receptors by pituitary adenylate cyclase activating peptide in CA1 neurons requires G alpha q, protein kinase C, and activation of Src. The Journal of neuroscience : the official journal of the Society for Neuroscience 2005 Dec 7;25(49):11374-84
  11. Bouschet T, Perez V, Fernandez C, Bockaert J, Eychene A, Journot L
    Stimulation of the ERK pathway by GTP-loaded Rap1 requires the concomitant activation of Ras, protein kinase C, and protein kinase A in neuronal cells. The Journal of biological chemistry 2003 Feb 14;278(7):4778-85
  12. Kiermayer S, Biondi RM, Imig J, Plotz G, Haupenthal J, Zeuzem S, Piiper A
    Epac activation converts cAMP from a proliferative into a differentiation signal in PC12 cells. Molecular biology of the cell 2005 Dec;16(12):5639-48
  13. Ster J, De Bock F, Guérineau NC, Janossy A, Barrère-Lemaire S, Bos JL, Bockaert J, Fagni L
    Exchange protein activated by cAMP (Epac) mediates cAMP activation of p38 MAPK and modulation of Ca2+-dependent K+ channels in cerebellar neurons. Proceedings of the National Academy of Sciences of the United States of America 2007 Feb 13;104(7):2519-24
  14. Kogure A, Sakane N, Takakura Y, Umekawa T, Yoshioka K, Nishino H, Yamamoto T, Kawada T, Yoshikawa T, Yoshida T
    Effects of caffeine on the uncoupling protein family in obese yellow KK mice. Clinical and experimental pharmacology & physiology 2002 May-Jun;29(5-6):391-4
  15. Hetman M, Gozdz A
    Role of extracellular signal regulated kinases 1 and 2 in neuronal survival. European journal of biochemistry / FEBS 2004 Jun;271(11):2050-5
  16. Zhang W, Smith A, Liu JP, Cheung NS, Zhou S, Liu K, Li QT, Duan W
    GSK3beta modulates PACAP-induced neuritogenesis in PC12 cells by acting downstream of Rap1 in a caveolae-dependent manner. Cellular signalling 2009 Feb;21(2):237-45
  17. Corbitt J, Vivekananda J, Wang SS, Strong R
    Transcriptional and posttranscriptional control of tyrosine hydroxylase gene expression during persistent stimulation of pituitary adenylate cyclase-activating polypeptide receptors on PC12 cells: regulation by protein kinase A-dependent and protein kinase A-independent pathways. Journal of neurochemistry 1998 Aug;71(2):478-86
  18. McIlvain HB, Baudy A, Sullivan K, Liu D, Pong K, Fennell M, Dunlop J
    Pituitary adenylate cyclase-activating peptide (PACAP) induces differentiation in the neuronal F11 cell line through a PKA-dependent pathway. Brain research 2006 Mar 10;1077(1):16-23
  19. Barrie AP, Clohessy AM, Buensuceso CS, Rogers MV, Allen JM
    Pituitary adenylyl cyclase-activating peptide stimulates extracellular signal-regulated kinase 1 or 2 (ERK1/2) activity in a Ras-independent, mitogen-activated protein Kinase/ERK kinase 1 or 2-dependent manner in PC12 cells. The Journal of biological chemistry 1997 Aug 8;272(32):19666-71
  20. Lazarovici P, Jiang H, Fink D Jr
    The 38-amino-acid form of pituitary adenylate cyclase-activating polypeptide induces neurite outgrowth in PC12 cells that is dependent on protein kinase C and extracellular signal-regulated kinase but not on protein kinase A, nerve growth factor receptor tyrosine kinase, p21(ras) G protein, and pp60(c-src) cytoplasmic tyrosine kinase. Molecular pharmacology 1998 Sep;54(3):547-58
  21. Watanabe J, Ohba M, Ohno F, Kikuyama S, Nakamura M, Nakaya K, Arimura A, Shioda S, Nakajo S
    Pituitary adenylate cyclase-activating polypeptide-induced differentiation of embryonic neural stem cells into astrocytes is mediated via the beta isoform of protein kinase C. Journal of neuroscience research 2006 Dec;84(8):1645-55
  22. Vaudry D, Gonzalez BJ, Basille M, Anouar Y, Fournier A, Vaudry H
    Pituitary adenylate cyclase-activating polypeptide stimulates both c-fos gene expression and cell survival in rat cerebellar granule neurons through activation of the protein kinase A pathway. Neuroscience 1998 Jun;84(3):801-12
  23. Vaudry D, Basille M, Anouar Y, Fournier A, Vaudry H, Gonzalez BJ
    The neurotrophic activity of PACAP on rat cerebellar granule cells is associated with activation of the protein kinase A pathway and c-fos gene expression. Annals of the New York Academy of Sciences 1998 Dec 11;865:92-9
  24. Tabuchi A, Koizumi M, Nakatsubo J, Yaguchi T, Tsuda M
    Involvement of endogenous PACAP expression in the activity-dependent survival of mouse cerebellar granule cells. Neuroscience research 2001 Jan;39(1):85-93
  25. Falluel-Morel A, Aubert N, Vaudry D, Basille M, Fontaine M, Fournier A, Vaudry H, Gonzalez BJ
    Opposite regulation of the mitochondrial apoptotic pathway by C2-ceramide and PACAP through a MAP-kinase-dependent mechanism in cerebellar granule cells. Journal of neurochemistry 2004 Dec;91(5):1231-43
  26. Aubert N, Falluel-Morel A, Vaudry D, Xifro X, Rodriguez-Alvarez J, Fisch C, de Jouffrey S, Lebigot JF, Fournier A, Vaudry H, Gonzalez BJ
    PACAP and C2-ceramide generate different AP-1 complexes through a MAP-kinase-dependent pathway: involvement of c-Fos in PACAP-induced Bcl-2 expression. Journal of neurochemistry 2006 Nov;99(4):1237-50
  27. Vaudry D, Gonzalez BJ, Basille M, Pamantung TF, Fontaine M, Fournier A, Vaudry H
    The neuroprotective effect of pituitary adenylate cyclase-activating polypeptide on cerebellar granule cells is mediated through inhibition of the CED3-related cysteine protease caspase-3/CPP32. Proceedings of the National Academy of Sciences of the United States of America 2000 Nov 21;97(24):13390-5
  28. Vaudry D, Falluel-Morel A, Basille M, Pamantung TF, Fontaine M, Fournier A, Vaudry H, Gonzalez BJ
    Pituitary adenylate cyclase-activating polypeptide prevents C2-ceramide-induced apoptosis of cerebellar granule cells. Journal of neuroscience research 2003 May 1;72(3):303-16
  29. Mei YA, Vaudry D, Basille M, Castel H, Fournier A, Vaudry H, Gonzalez BJ
    PACAP inhibits delayed rectifier potassium current via a cAMP/PKA transduction pathway: evidence for the involvement of I k in the anti-apoptotic action of PACAP. The European journal of neuroscience 2004 Mar;19(6):1446-58
  30. Vaudry D, Hamelink C, Damadzic R, Eskay RL, Gonzalez B, Eiden LE
    Endogenous PACAP acts as a stress response peptide to protect cerebellar neurons from ethanol or oxidative insult. Peptides 2005 Dec;26(12):2518-24

  1. Vaudry D, Gonzalez BJ, Basille M, Yon L, Fournier A, Vaudry H
    Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacological reviews 2000 Jun;52(2):269-324
  2. Vaudry D, Stork PJ, Lazarovici P, Eiden LE
    Signaling pathways for PC12 cell differentiation: making the right connections. Science (New York, N.Y.) 2002 May 31;296(5573):1648-9
  3. Botia B, Basille M, Allais A, Raoult E, Falluel-Morel A, Galas L, Jolivel V, Wurtz O, Komuro H, Fournier A, Vaudry H, Burel D, Gonzalez BJ, Vaudry D
    Neurotrophic effects of PACAP in the cerebellar cortex. Peptides 2007 Sep;28(9):1746-52
  4. Pisegna JR, Wank SA
    Cloning and characterization of the signal transduction of four splice variants of the human pituitary adenylate cyclase activating polypeptide receptor. Evidence for dual coupling to adenylate cyclase and phospholipase C. The Journal of biological chemistry 1996 Jul 19;271(29):17267-74
  5. Ravni A, Bourgault S, Lebon A, Chan P, Galas L, Fournier A, Vaudry H, Gonzalez B, Eiden LE, Vaudry D
    The neurotrophic effects of PACAP in PC12 cells: control by multiple transduction pathways. Journal of neurochemistry 2006 Jul;98(2):321-9
  6. Deutsch PJ, Sun Y
    The 38-amino acid form of pituitary adenylate cyclase-activating polypeptide stimulates dual signaling cascades in PC12 cells and promotes neurite outgrowth. The Journal of biological chemistry 1992 Mar 15;267(8):5108-13
  7. Hezareh M, Schlegel W, Rawlings SR
    PACAP and VIP stimulate Ca2+ oscillations in rat gonadotrophs through the PACAP/VIP type 1 receptor (PVR1) linked to a pertussis toxin-insensitive G-protein and the activation of phospholipase C-beta. Journal of neuroendocrinology 1996 May;8(5):367-74
  8. Van Rampelbergh J, Poloczek P, Françoys I, Delporte C, Winand J, Robberecht P, Waelbroeck M
    The pituitary adenylate cyclase activating polypeptide (PACAP I) and VIP (PACAP II VIP1) receptors stimulate inositol phosphate synthesis in transfected CHO cells through interaction with different G proteins. Biochimica et biophysica acta 1997 Jun 27;1357(2):249-55
  9. Zhou CJ, Yada T, Kohno D, Kikuyama S, Suzuki R, Mizushima H, Shioda S
    PACAP activates PKA, PKC and Ca(2+) signaling cascades in rat neuroepithelial cells. Peptides 2001 Jul;22(7):1111-7
  10. Macdonald DS, Weerapura M, Beazely MA, Martin L, Czerwinski W, Roder JC, Orser BA, MacDonald JF
    Modulation of NMDA receptors by pituitary adenylate cyclase activating peptide in CA1 neurons requires G alpha q, protein kinase C, and activation of Src. The Journal of neuroscience : the official journal of the Society for Neuroscience 2005 Dec 7;25(49):11374-84
  11. Bouschet T, Perez V, Fernandez C, Bockaert J, Eychene A, Journot L
    Stimulation of the ERK pathway by GTP-loaded Rap1 requires the concomitant activation of Ras, protein kinase C, and protein kinase A in neuronal cells. The Journal of biological chemistry 2003 Feb 14;278(7):4778-85
  12. Kiermayer S, Biondi RM, Imig J, Plotz G, Haupenthal J, Zeuzem S, Piiper A
    Epac activation converts cAMP from a proliferative into a differentiation signal in PC12 cells. Molecular biology of the cell 2005 Dec;16(12):5639-48
  13. Ster J, De Bock F, Guérineau NC, Janossy A, Barrère-Lemaire S, Bos JL, Bockaert J, Fagni L
    Exchange protein activated by cAMP (Epac) mediates cAMP activation of p38 MAPK and modulation of Ca2+-dependent K+ channels in cerebellar neurons. Proceedings of the National Academy of Sciences of the United States of America 2007 Feb 13;104(7):2519-24
  14. Kogure A, Sakane N, Takakura Y, Umekawa T, Yoshioka K, Nishino H, Yamamoto T, Kawada T, Yoshikawa T, Yoshida T
    Effects of caffeine on the uncoupling protein family in obese yellow KK mice. Clinical and experimental pharmacology & physiology 2002 May-Jun;29(5-6):391-4
  15. Hetman M, Gozdz A
    Role of extracellular signal regulated kinases 1 and 2 in neuronal survival. European journal of biochemistry / FEBS 2004 Jun;271(11):2050-5
  16. Zhang W, Smith A, Liu JP, Cheung NS, Zhou S, Liu K, Li QT, Duan W
    GSK3beta modulates PACAP-induced neuritogenesis in PC12 cells by acting downstream of Rap1 in a caveolae-dependent manner. Cellular signalling 2009 Feb;21(2):237-45
  17. Corbitt J, Vivekananda J, Wang SS, Strong R
    Transcriptional and posttranscriptional control of tyrosine hydroxylase gene expression during persistent stimulation of pituitary adenylate cyclase-activating polypeptide receptors on PC12 cells: regulation by protein kinase A-dependent and protein kinase A-independent pathways. Journal of neurochemistry 1998 Aug;71(2):478-86
  18. McIlvain HB, Baudy A, Sullivan K, Liu D, Pong K, Fennell M, Dunlop J
    Pituitary adenylate cyclase-activating peptide (PACAP) induces differentiation in the neuronal F11 cell line through a PKA-dependent pathway. Brain research 2006 Mar 10;1077(1):16-23
  19. Barrie AP, Clohessy AM, Buensuceso CS, Rogers MV, Allen JM
    Pituitary adenylyl cyclase-activating peptide stimulates extracellular signal-regulated kinase 1 or 2 (ERK1/2) activity in a Ras-independent, mitogen-activated protein Kinase/ERK kinase 1 or 2-dependent manner in PC12 cells. The Journal of biological chemistry 1997 Aug 8;272(32):19666-71
  20. Lazarovici P, Jiang H, Fink D Jr
    The 38-amino-acid form of pituitary adenylate cyclase-activating polypeptide induces neurite outgrowth in PC12 cells that is dependent on protein kinase C and extracellular signal-regulated kinase but not on protein kinase A, nerve growth factor receptor tyrosine kinase, p21(ras) G protein, and pp60(c-src) cytoplasmic tyrosine kinase. Molecular pharmacology 1998 Sep;54(3):547-58
  21. Watanabe J, Ohba M, Ohno F, Kikuyama S, Nakamura M, Nakaya K, Arimura A, Shioda S, Nakajo S
    Pituitary adenylate cyclase-activating polypeptide-induced differentiation of embryonic neural stem cells into astrocytes is mediated via the beta isoform of protein kinase C. Journal of neuroscience research 2006 Dec;84(8):1645-55
  22. Vaudry D, Gonzalez BJ, Basille M, Anouar Y, Fournier A, Vaudry H
    Pituitary adenylate cyclase-activating polypeptide stimulates both c-fos gene expression and cell survival in rat cerebellar granule neurons through activation of the protein kinase A pathway. Neuroscience 1998 Jun;84(3):801-12
  23. Vaudry D, Basille M, Anouar Y, Fournier A, Vaudry H, Gonzalez BJ
    The neurotrophic activity of PACAP on rat cerebellar granule cells is associated with activation of the protein kinase A pathway and c-fos gene expression. Annals of the New York Academy of Sciences 1998 Dec 11;865:92-9
  24. Tabuchi A, Koizumi M, Nakatsubo J, Yaguchi T, Tsuda M
    Involvement of endogenous PACAP expression in the activity-dependent survival of mouse cerebellar granule cells. Neuroscience research 2001 Jan;39(1):85-93
  25. Falluel-Morel A, Aubert N, Vaudry D, Basille M, Fontaine M, Fournier A, Vaudry H, Gonzalez BJ
    Opposite regulation of the mitochondrial apoptotic pathway by C2-ceramide and PACAP through a MAP-kinase-dependent mechanism in cerebellar granule cells. Journal of neurochemistry 2004 Dec;91(5):1231-43
  26. Aubert N, Falluel-Morel A, Vaudry D, Xifro X, Rodriguez-Alvarez J, Fisch C, de Jouffrey S, Lebigot JF, Fournier A, Vaudry H, Gonzalez BJ
    PACAP and C2-ceramide generate different AP-1 complexes through a MAP-kinase-dependent pathway: involvement of c-Fos in PACAP-induced Bcl-2 expression. Journal of neurochemistry 2006 Nov;99(4):1237-50
  27. Vaudry D, Gonzalez BJ, Basille M, Pamantung TF, Fontaine M, Fournier A, Vaudry H
    The neuroprotective effect of pituitary adenylate cyclase-activating polypeptide on cerebellar granule cells is mediated through inhibition of the CED3-related cysteine protease caspase-3/CPP32. Proceedings of the National Academy of Sciences of the United States of America 2000 Nov 21;97(24):13390-5
  28. Vaudry D, Falluel-Morel A, Basille M, Pamantung TF, Fontaine M, Fournier A, Vaudry H, Gonzalez BJ
    Pituitary adenylate cyclase-activating polypeptide prevents C2-ceramide-induced apoptosis of cerebellar granule cells. Journal of neuroscience research 2003 May 1;72(3):303-16
  29. Mei YA, Vaudry D, Basille M, Castel H, Fournier A, Vaudry H, Gonzalez BJ
    PACAP inhibits delayed rectifier potassium current via a cAMP/PKA transduction pathway: evidence for the involvement of I k in the anti-apoptotic action of PACAP. The European journal of neuroscience 2004 Mar;19(6):1446-58
  30. Vaudry D, Hamelink C, Damadzic R, Eskay RL, Gonzalez B, Eiden LE
    Endogenous PACAP acts as a stress response peptide to protect cerebellar neurons from ethanol or oxidative insult. Peptides 2005 Dec;26(12):2518-24

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