Membrane toxicity of the protein kinase C inhibitor calphostin A by a free-radical mechanism

Samuel S.H. Wang, Chris Mathes, Stuart H. Thompson

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The effects of calphostin A on cytoplasmic calcium levels, receptor-mediated calcium release, and membrane input resistance were measured in neuroblastoma cells. Calphostin A is a lipophilic, light-sensitive perylenequinone that generates singlet oxygen when illuminated. It inhibits the activity of protein kinase C (IC50 = 250 nM), but only in the presence of light. Phorbol esters normally attenuate carbachol-evoked calcium release. This effect was blocked by simultaneous exposure to light and calphostin A (40 nM) for 30 min. At higher doses (0.5-1 μM) calphostin A also approximately doubled the resting calcium level and decreased cell input resistance by 51%. These toxic effects did not occur in the dark or after preincubation with the antioxidant α-tocopherol. These data support the hypothesis that the calphostins act by partitioning into the membrane and producing singlet oxygen and endoperoxides which then irreversibly modify protein kinase C and other membrane proteins and lipids.

Original languageEnglish (US)
Pages (from-to)145-148
Number of pages4
JournalNeuroscience Letters
Volume156
Issue number1-2
DOIs
StatePublished - Jun 25 1993
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • Calphostin
  • Free radical
  • Kinase inhibitors
  • Muscarinic acetylcholine receptor
  • Photoxicity
  • Protein kinase C
  • Singlet oxygen

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