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Cholesterol enhances neuron susceptibility to apoptotic stimuli via cAMP/PKA/CREB‐dependent up‐regulation of Kv2.1
Author(s) -
Zhou MengHua,
Yang Guang,
Jiao Song,
Hu ChangLong,
Mei YanAi
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07593.x
Subject(s) - creb , apoptosis , cholesterol , lipid raft , long term potentiation , microbiology and biotechnology , dna fragmentation , chemistry , biology , medicine , programmed cell death , endocrinology , biochemistry , receptor , transcription factor , gene
J. Neurochem. (2012) 120 , 502–514. 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 5 mM 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 25 mM 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.