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Ceramide inhibits inwardly rectifying K+ currents via a Ras- and Raf-1-dependent pathway in cultured oligodendrocytes

H Hida1, M Takeda, B Soliven

  • 1Department of Neurology, The Brain Research Institute, The University of Chicago, Chicago, Illinois 60637, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|October 24, 1998
PubMed

Insights

Ceramide (cer) affects transmembrane signaling in oligodendrocytes (OLGs). It inhibits inwardly rectifying K+ currents (IKir) via a Ras- and raf-1-dependent pathway, leading to OLG depolarization.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Ceramide (cer) is a lipid mediator involved in apoptosis induced by proinflammatory cytokines.
  • Oligodendrocytes (OLGs) are crucial glial cells in the central nervous system.
  • Transmembrane signaling events are critical for OLG function and survival.

Purpose of the Study:

  • To investigate the effect of ceramide on transmembrane signaling in cultured neonatal rat oligodendrocytes (OLGs).
  • To determine ceramide's impact on intracellular calcium (Cai), resting membrane potential, and inwardly rectifying K+ currents (IKir).

Main Methods:

  • Cultured neonatal rat oligodendrocytes (OLGs) were treated with C2-ceramide (cer) and related compounds.
  • Intracellular calcium (Cai) levels were measured.
  • Resting membrane potential and inwardly rectifying K+ currents (IKir) were electrophysiologically assessed.
  • Specific inhibitors and antisense oligonucleotides targeting Ras and raf-1 pathways were employed.

Main Results:

  • C2-ceramide (cer) rarely increased OLG intracellular calcium (Cai), unlike sphingosine.
  • Ceramide caused OLG depolarization, an effect mimicked by sphingosine-1-phosphate.
  • Ceramide inhibited OLG inwardly rectifying K+ currents (IKir), an effect not observed with dihydroceramide.
  • The ceramide-induced inhibition of IKir was attenuated by Ras antibody, protein kinase C inhibitory peptide, and suppression of c-Raf-1 expression.

Conclusions:

  • Ceramide modulates transmembrane signaling in oligodendrocytes (OLGs).
  • Ceramide-induced OLG depolarization is mediated by the inhibition of inwardly rectifying K+ currents (IKir).
  • This inhibition involves a Ras- and raf-1-dependent pathway, leading to the phosphorylation of the inward rectifier K+ channel protein.

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