title: Cholesterol enhances neuron susceptibility to apoptotic stimuli via cAMP/PKA/CREB-dependent up-regulation of Kv2.1.
abstract: 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.
authors: Institutes of Brain Science, School of Life Sciences and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors: Meng-Hua
authors: MH
authors: Zhou
authors: Guang
authors: G
authors: Yang
authors: Song
authors: S
authors: Jiao
authors: Chang-Long
authors: CL
authors: Hu
authors: Yan-Ai
authors: YA
authors: Mei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D050882:CREB-Binding Protein / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051669:Shab Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C496991:Kcnb1 protein, rat; D051669:Shab Potassium Channels; D002784:Cholesterol; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases