Cholesterol enhances neuron susceptibility to apoptotic stimuli via cAMP/PKA/CREB-dependent up-regulation of Kv2.1

J Neurochem. 2012 Feb;120(4):502-14. doi: 10.1111/j.1471-4159.2011.07593.x.


Cholesterol is a major component of membrane lipid rafts. It is more abundant in the brain than in other tissues and plays a critical role in maintaining brain function. We report here that a significant enhancement in apoptosis in rat cerebellar granule neurons (CGNs) was observed upon incubation with 5mM K(+) /serum free (LK-S) medium. Cholesterol enrichment further potentiated CGN apoptosis incubated under LK-S medium. On the contrary, cholesterol depletion using methyl-beta-cyclodextrin protected the CGNs from apoptosis induced by LK-S treatment. Cholesterol enrichment, however, did not induce apoptosis in CGNs that have been incubated with 25mM K(+) /serum medium. Mechanistically, increased I(K) currents and DNA fragmentation were found in CGNs incubated in LK-S, which was further potentiated in the presence of cholesterol. Cholesterol-treated CGNs also exhibited increased cAMP levels and up-regulation of Kv2.1 expression. Increased levels of activated form of PKA and phospho-CREB further supported activation of the cAMP/PKA pathway upon treatment of CGNs with cholesterol-containing LK-S medium. Conversely, inhibition of PKA or small G protein Gs abolished the increase in I(K) current and the potentiation of Kv2.1 expression, leading to reduced susceptibility of CGNs to LK-S and cholesterol-induced apoptosis. Our results demonstrate that the elevation of membrane cholesterol enhances CGN susceptibility to apoptotic stimuli via cAMP/PKA/CREB-dependent up-regulation of Kv2.1. Our data provide new evidence for the role of cholesterol in eliciting neuronal cell death.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • CREB-Binding Protein / metabolism*
  • Cells, Cultured
  • Cholesterol / physiology*
  • Cyclic AMP / physiology
  • Cyclic AMP-Dependent Protein Kinases / physiology*
  • Female
  • Genetic Predisposition to Disease
  • Neurons / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Shab Potassium Channels / biosynthesis*
  • Shab Potassium Channels / genetics
  • Signal Transduction / genetics
  • Up-Regulation / physiology*


  • Kcnb1 protein, rat
  • Shab Potassium Channels
  • Cholesterol
  • Cyclic AMP
  • CREB-Binding Protein
  • Crebbp protein, rat
  • Cyclic AMP-Dependent Protein Kinases