PMID- 17641674
OWN - NLM
STAT- MEDLINE
DCOM- 20071218
LR  - 20181113
IS  - 0007-1188 (Print)
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Linking)
VI  - 152
IP  - 2
DP  - 2007 Sep
TI  - Mitogen-activated protein kinases regulate palytoxin-induced calcium influx and 
      cytotoxicity in cultured neurons.
PG  - 256-66
AB  - BACKGROUND AND PURPOSE: Palytoxin (PLT) is a potent toxin that binds to the 
      Na,K-ATPase. Palytoxin is highly neurotoxic and increases the cytosolic calcium 
      concentration ([Ca(2+)](c)) while decreasing intracellular pH (pH(i)) in neurons 
      (Vale et al., 2006; Vale-Gonzalez et al., 2007). It is also a tumour promoter 
      that activates several protein kinases. EXPERIMENTAL APPROACH: The role of 
      different protein kinases in the effects of palytoxin on [Ca(2+)](c), pH(i) and 
      cytoxicity was investigated in cultured neurons. KEY RESULTS: Palytoxin-induced 
      calcium load was not affected by inhibition of calcium-dependent protein kinase C 
      (PKC) isoforms but it was partially ameliorated by blockade of 
      calcium-independent PKC isozymes. Inhibition of the extracellular 
      signal-regulated kinase (ERK) 2 eliminated the palytoxin-induced rise in calcium 
      and intracellular acidification, whereas inhibition of MEK greatly attenuated the 
      palytoxin effect on calcium without modifying the PLT-evoked intracellular 
      acidification. Blockade of c-Jun N-terminal protein kinases (JNK) somewhat 
      decreased the palytoxin-effect on calcium, whereas inhibition of the p38 mitogen 
      activated protein kinases (MAPKs) delayed the onset of the palytoxin-evoked rise 
      in calcium and acidification. Furthermore, the cytotoxicity of palytoxin was 
      completely blocked by inhibition of ERK 2 and partially prevented by inhibition 
      of MEK. PLT increased phosphorylated ERK immunoreactivity in a 
      concentration-dependent manner. CONCLUSIONS AND IMPLICATIONS: MAPKs, specifically 
      ERK 2, link palytoxin cytotoxicity with its effects on calcium homeostasis after 
      inhibition of the Na,K-ATPase. Binding of palytoxin to the Na,K-ATPase would 
      alter signal transduction pathways, even in non-dividing cells, and this finding 
      is related to the potent neurotoxicity of this marine toxin.
FAU - Vale, C
AU  - Vale C
AD  - Departamento de Farmacologia, Facultad de Veterinaria, USC, Campus Universitario 
      s/n, Lugo, Spain.
FAU - Gomez-Limia, B
AU  - Gomez-Limia B
FAU - Vieytes, M R
AU  - Vieytes MR
FAU - Botana, L M
AU  - Botana LM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070716
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Acrylamides)
RN  - 0 (Cnidarian Venoms)
RN  - 0 (Neurotoxins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - OQ17NC0MOV (palytoxin)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Acrylamides/*pharmacology
MH  - Animals
MH  - Calcium/*metabolism
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cerebellum/cytology
MH  - Cnidarian Venoms/pharmacology
MH  - Mice
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Neurons/*drug effects/metabolism
MH  - Neurotoxins/*toxicity
MH  - Protein Kinase Inhibitors/pharmacology
PMC - PMC1978258
EDAT- 2007/07/21 09:00
MHDA- 2007/12/19 09:00
PMCR- 2008/09/01
CRDT- 2007/07/21 09:00
PHST- 2007/07/21 09:00 [pubmed]
PHST- 2007/12/19 09:00 [medline]
PHST- 2007/07/21 09:00 [entrez]
PHST- 2008/09/01 00:00 [pmc-release]
AID - 0707389 [pii]
AID - 10.1038/sj.bjp.0707389 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2007 Sep;152(2):256-66. doi: 10.1038/sj.bjp.0707389. Epub 2007 
      Jul 16.