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Depolarization regulates cyclin D1 degradation and neuronal apoptosis: a hypothesis about the role of the ubiquitin/proteasome signalling pathway
Author(s) -
Boutillier AnneLaurence,
KienlenCampard Pascal,
Loeffler JeanPhilippe
Publication year - 1999
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1999.00451.x
Subject(s) - microbiology and biotechnology , camk , lactacystin , proteasome , calcium signaling , biology , neuroprotection , calmodulin , apoptosis , depolarization , programmed cell death , calcium , signal transduction , chemistry , proteasome inhibitor , biochemistry , kinase , protein kinase a , pharmacology , endocrinology , organic chemistry , autophosphorylation , enzyme
Depolarization and subsequent calcium entry exert essential neuroprotective effects but the ultimate effector by which calcium blocks apoptosis is not known. Here we show that inhibition of calcium entry into cerebellar neurons by switching from high to low extracellular K + concentrations (30–5 m m ) induces apoptosis, that correlates with a rapid accumulation of cyclin D1 (CD1), an early marker of the G 1 /S transition of the cell cycle. These effects on apoptosis and cyclin D1 are mimicked either by blocking calcium entry into neurons (LaCl 3 , 100 μ m or nifedipine, 10 –6 m ) or by inhibiting the calcium/calmodulin pathway (calmidazolium, 10 –7 m ). The increased CD1 protein levels do not result from a transcriptional upregulation of the CD1 gene by the Ca 2+ /calmodulin pathway but rather reflect an accumulation due to the lack of degradation by the proteasome‐dependent pathway. Specific proteasome antagonists: carbobenzoxyl‐leucinyl‐leucinyl‐norvalinal‐H (MG‐115), carbobenzoxyl‐leucinyl‐leucinyl‐leucinal‐H (MG‐132) and clasto‐lactacystin β‐lactone, induce neuronal apoptosis by themselves. Finally, this pathway is functional only at neuroprotective concentrations of K + (30 m m ), suggesting that calcium/CamK signalling pathway may regulate neuronal death by regulating the proteasome‐mediated degradation activity of rapidly turning‐over proteins (constitutively expressed genes or pre‐existing pools of mRNA).