Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca 2+-MAPK/ERK pathways

François Lallemend, P. P. Lefebvre, G. Hans, J. M. Rigo, Thomas R Van De Water, G. Moonen, B. Malgrange

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

In the current study, we have investigated the ability of substance P (SP) to protect 3-day-old (P3) rat spiral ganglion neurons (SGNs) from trophic factor deprivation (TFD)-induced cell death. The presence of SP high affinity neurokinin-1 receptor (NK1) transcripts was detected in the spiral ganglion and the NK1 protein localized to SGNs both ex vivo and in vitro. Treatment with SP increased cytoplasmic Ca2+ in SGNs, further arguing for the presence of functional NK1 on these neurons. Both SP and the agonist [Sar 9,Met(O2)11]-SP significantly decreased SGN cell death induced by TFD, with no effect on neurite outgrowth. The survival promoting effect of SP was blocked by the NK1 antagonist, WIN51708. Both pan-caspase inhibitor BOC-D-FMK and SP treatments markedly reduced activation of caspases and DNA fragmentation in trophic factor deprived-neurons. The neuroprotective action of SP was antagonised by specific inhibitors of second messengers, including 1.2.bis-(O-aminophenoxy)-ethane-N,N,N′,N′ -tetraacetic acid (BAPTA-AM) to chelate cytosolic Ca2+, the protein kinase C (PKC) inhibitors bisindolylmaleimide I, Gö6976 and LY333531 and the MAPK/ERK inhibitor U0126. In contrast, nifedipine, a specific inhibitor of L-type Ca2+ channel, and LY294002, a phosphatidylinositol-3-OH kinase (PI3K) inhibitor, had no effect on SP trophic support of SGNs. Moreover, activation of endogenous PKC by 4β-phorbol 12-myristate 13-acetate (PMA) also reduced the loss of trophic factor-deprived SGNs. Thus, NK1 expressed by SGNs transmit a survival-promoting regulatory signal during TFD-induced SGN cell death via pathways involving PKC activation, Ca2+ signalling and MAPK/ERK activation, which can be accounted for by an inhibition of caspase activation.

Original languageEnglish
Pages (from-to)508-521
Number of pages14
JournalJournal of Neurochemistry
Volume87
Issue number2
DOIs
StatePublished - Oct 1 2003

Fingerprint

Spiral Ganglion
MAP Kinase Signaling System
Substance P
Protein Kinase C
Neurons
Apoptosis
Neurokinin-1 Receptors
Chemical activation
Cell death
Cell Death
Caspases
ruboxistaurin
Neurokinin-1 Receptor Antagonists
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Ethane
Caspase Inhibitors
Protein C Inhibitor
Second Messenger Systems
DNA Fragmentation
Nifedipine

Keywords

  • Apoptosis
  • Neuroprotection
  • NK1
  • Spiral ganglion neurons
  • Substance P

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Lallemend, F., Lefebvre, P. P., Hans, G., Rigo, J. M., Van De Water, T. R., Moonen, G., & Malgrange, B. (2003). Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca 2+-MAPK/ERK pathways. Journal of Neurochemistry, 87(2), 508-521. https://doi.org/10.1046/j.1471-4159.2003.02014.x

Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca 2+-MAPK/ERK pathways. / Lallemend, François; Lefebvre, P. P.; Hans, G.; Rigo, J. M.; Van De Water, Thomas R; Moonen, G.; Malgrange, B.

In: Journal of Neurochemistry, Vol. 87, No. 2, 01.10.2003, p. 508-521.

Research output: Contribution to journalArticle

Lallemend, F, Lefebvre, PP, Hans, G, Rigo, JM, Van De Water, TR, Moonen, G & Malgrange, B 2003, 'Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca 2+-MAPK/ERK pathways', Journal of Neurochemistry, vol. 87, no. 2, pp. 508-521. https://doi.org/10.1046/j.1471-4159.2003.02014.x
Lallemend, François ; Lefebvre, P. P. ; Hans, G. ; Rigo, J. M. ; Van De Water, Thomas R ; Moonen, G. ; Malgrange, B. / Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca 2+-MAPK/ERK pathways. In: Journal of Neurochemistry. 2003 ; Vol. 87, No. 2. pp. 508-521.
@article{90a3e2b9ec00441da4a6036b3ddabe2f,
title = "Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca 2+-MAPK/ERK pathways",
abstract = "In the current study, we have investigated the ability of substance P (SP) to protect 3-day-old (P3) rat spiral ganglion neurons (SGNs) from trophic factor deprivation (TFD)-induced cell death. The presence of SP high affinity neurokinin-1 receptor (NK1) transcripts was detected in the spiral ganglion and the NK1 protein localized to SGNs both ex vivo and in vitro. Treatment with SP increased cytoplasmic Ca2+ in SGNs, further arguing for the presence of functional NK1 on these neurons. Both SP and the agonist [Sar 9,Met(O2)11]-SP significantly decreased SGN cell death induced by TFD, with no effect on neurite outgrowth. The survival promoting effect of SP was blocked by the NK1 antagonist, WIN51708. Both pan-caspase inhibitor BOC-D-FMK and SP treatments markedly reduced activation of caspases and DNA fragmentation in trophic factor deprived-neurons. The neuroprotective action of SP was antagonised by specific inhibitors of second messengers, including 1.2.bis-(O-aminophenoxy)-ethane-N,N,N′,N′ -tetraacetic acid (BAPTA-AM) to chelate cytosolic Ca2+, the protein kinase C (PKC) inhibitors bisindolylmaleimide I, G{\"o}6976 and LY333531 and the MAPK/ERK inhibitor U0126. In contrast, nifedipine, a specific inhibitor of L-type Ca2+ channel, and LY294002, a phosphatidylinositol-3-OH kinase (PI3K) inhibitor, had no effect on SP trophic support of SGNs. Moreover, activation of endogenous PKC by 4β-phorbol 12-myristate 13-acetate (PMA) also reduced the loss of trophic factor-deprived SGNs. Thus, NK1 expressed by SGNs transmit a survival-promoting regulatory signal during TFD-induced SGN cell death via pathways involving PKC activation, Ca2+ signalling and MAPK/ERK activation, which can be accounted for by an inhibition of caspase activation.",
keywords = "Apoptosis, Neuroprotection, NK1, Spiral ganglion neurons, Substance P",
author = "Fran{\cc}ois Lallemend and Lefebvre, {P. P.} and G. Hans and Rigo, {J. M.} and {Van De Water}, {Thomas R} and G. Moonen and B. Malgrange",
year = "2003",
month = "10",
day = "1",
doi = "10.1046/j.1471-4159.2003.02014.x",
language = "English",
volume = "87",
pages = "508--521",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca 2+-MAPK/ERK pathways

AU - Lallemend, François

AU - Lefebvre, P. P.

AU - Hans, G.

AU - Rigo, J. M.

AU - Van De Water, Thomas R

AU - Moonen, G.

AU - Malgrange, B.

PY - 2003/10/1

Y1 - 2003/10/1

N2 - In the current study, we have investigated the ability of substance P (SP) to protect 3-day-old (P3) rat spiral ganglion neurons (SGNs) from trophic factor deprivation (TFD)-induced cell death. The presence of SP high affinity neurokinin-1 receptor (NK1) transcripts was detected in the spiral ganglion and the NK1 protein localized to SGNs both ex vivo and in vitro. Treatment with SP increased cytoplasmic Ca2+ in SGNs, further arguing for the presence of functional NK1 on these neurons. Both SP and the agonist [Sar 9,Met(O2)11]-SP significantly decreased SGN cell death induced by TFD, with no effect on neurite outgrowth. The survival promoting effect of SP was blocked by the NK1 antagonist, WIN51708. Both pan-caspase inhibitor BOC-D-FMK and SP treatments markedly reduced activation of caspases and DNA fragmentation in trophic factor deprived-neurons. The neuroprotective action of SP was antagonised by specific inhibitors of second messengers, including 1.2.bis-(O-aminophenoxy)-ethane-N,N,N′,N′ -tetraacetic acid (BAPTA-AM) to chelate cytosolic Ca2+, the protein kinase C (PKC) inhibitors bisindolylmaleimide I, Gö6976 and LY333531 and the MAPK/ERK inhibitor U0126. In contrast, nifedipine, a specific inhibitor of L-type Ca2+ channel, and LY294002, a phosphatidylinositol-3-OH kinase (PI3K) inhibitor, had no effect on SP trophic support of SGNs. Moreover, activation of endogenous PKC by 4β-phorbol 12-myristate 13-acetate (PMA) also reduced the loss of trophic factor-deprived SGNs. Thus, NK1 expressed by SGNs transmit a survival-promoting regulatory signal during TFD-induced SGN cell death via pathways involving PKC activation, Ca2+ signalling and MAPK/ERK activation, which can be accounted for by an inhibition of caspase activation.

AB - In the current study, we have investigated the ability of substance P (SP) to protect 3-day-old (P3) rat spiral ganglion neurons (SGNs) from trophic factor deprivation (TFD)-induced cell death. The presence of SP high affinity neurokinin-1 receptor (NK1) transcripts was detected in the spiral ganglion and the NK1 protein localized to SGNs both ex vivo and in vitro. Treatment with SP increased cytoplasmic Ca2+ in SGNs, further arguing for the presence of functional NK1 on these neurons. Both SP and the agonist [Sar 9,Met(O2)11]-SP significantly decreased SGN cell death induced by TFD, with no effect on neurite outgrowth. The survival promoting effect of SP was blocked by the NK1 antagonist, WIN51708. Both pan-caspase inhibitor BOC-D-FMK and SP treatments markedly reduced activation of caspases and DNA fragmentation in trophic factor deprived-neurons. The neuroprotective action of SP was antagonised by specific inhibitors of second messengers, including 1.2.bis-(O-aminophenoxy)-ethane-N,N,N′,N′ -tetraacetic acid (BAPTA-AM) to chelate cytosolic Ca2+, the protein kinase C (PKC) inhibitors bisindolylmaleimide I, Gö6976 and LY333531 and the MAPK/ERK inhibitor U0126. In contrast, nifedipine, a specific inhibitor of L-type Ca2+ channel, and LY294002, a phosphatidylinositol-3-OH kinase (PI3K) inhibitor, had no effect on SP trophic support of SGNs. Moreover, activation of endogenous PKC by 4β-phorbol 12-myristate 13-acetate (PMA) also reduced the loss of trophic factor-deprived SGNs. Thus, NK1 expressed by SGNs transmit a survival-promoting regulatory signal during TFD-induced SGN cell death via pathways involving PKC activation, Ca2+ signalling and MAPK/ERK activation, which can be accounted for by an inhibition of caspase activation.

KW - Apoptosis

KW - Neuroprotection

KW - NK1

KW - Spiral ganglion neurons

KW - Substance P

UR - http://www.scopus.com/inward/record.url?scp=0141884369&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0141884369&partnerID=8YFLogxK

U2 - 10.1046/j.1471-4159.2003.02014.x

DO - 10.1046/j.1471-4159.2003.02014.x

M3 - Article

VL - 87

SP - 508

EP - 521

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 2

ER -