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Mitogen-activated protein kinases regulate palytoxin-induced calcium influx and cytotoxicity in cultured neurons

C Vale1, B Gómez-Limia, M R Vieytes

  • 1Departamento de Farmacología, Facultad de Veterinaria, USC, Campus Universitario s/n, Lugo, Spain.

British Journal of Pharmacology
|July 21, 2007
PubMed
Abstract

Insights

Palytoxin (PLT) neurotoxicity is linked to its effects on calcium and pH via mitogen-activated protein kinases (MAPKs), particularly ERK 2. Inhibiting ERK 2 blocks PLT

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Toxicology

Background:

  • Palytoxin (PLT) is a potent neurotoxin that binds to the Na,K-ATPase.
  • PLT disrupts neuronal calcium homeostasis and intracellular pH, and acts as a tumor promoter.
  • PLT activates various protein kinases, suggesting a role in its cellular effects.

Purpose of the Study:

  • To investigate the role of different protein kinases in mediating palytoxin's effects on neuronal calcium, pH, and cytotoxicity.
  • To elucidate the specific signaling pathways involved in palytoxin's neurotoxic actions.

Main Methods:

  • Cultured neurons were treated with palytoxin and various kinase inhibitors.
  • Measurements included intracellular calcium concentration ([Ca(2+)](c)), intracellular pH (pH(i)), and cytotoxicity.
  • Western blotting was used to assess protein phosphorylation, specifically of ERK.

Main Results:

  • Inhibition of extracellular signal-regulated kinase 2 (ERK 2) completely abolished palytoxin-induced calcium increase, acidification, and cytotoxicity.
  • MEK inhibition partially reduced palytoxin's effect on calcium but not pH, while p38 MAPK inhibition delayed the onset of palytoxin's effects.
  • Palytoxin exposure led to a concentration-dependent increase in phosphorylated ERK.

Conclusions:

  • Mitogen-activated protein kinases (MAPKs), especially ERK 2, are critical mediators linking palytoxin cytotoxicity to disrupted calcium homeostasis.
  • Palytoxin binding to Na,K-ATPase initiates signal transduction alterations, contributing to its potent neurotoxicity.
  • These findings highlight the role of signal transduction pathways in the cellular effects of palytoxin.

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