Nitric Oxide-GAPDH Transcriptional Signaling Mediates Behavioral Actions of Cocaine.
CNS Neurol Disord Drug Targets
; 14(6): 757-63, 2015.
Article
em En
| MEDLINE
| ID: mdl-26022259
ABSTRACT
Psychotropic actions of cocaine are generally thought to involve its blockade of monoamine transporters leading to increased synaptic levels of monoamines, especially dopamine. Subsequent intracellular events have been less well characterized. We describe a signaling system wherein lower behavioral stimulant doses of cocaine, as well as higher neurotoxic doses, activate a cascade wherein nitric oxide nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to generate a complex with the ubiquitin-E3-ligase Siah1 which translocates to the nucleus. With lower cocaine doses, nuclear GAPDH augments CREB signaling, while at higher doses p53 signaling is enhanced. The drug CGP3466B very potently blocks GAPDH nitrosylation, hindering both signaling cascades and inhibits both behavioral activating and neurotoxic effects of cocaine. This system affords potentially novel approaches to the therapy of cocaine abuse.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Cocaína
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Inibidores da Captação de Dopamina
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Gliceraldeído-3-Fosfato Desidrogenases
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Óxido Nítrico
Limite:
Animals
/
Humans
Idioma:
En
Revista:
CNS Neurol Disord Drug Targets
Assunto da revista:
NEUROLOGIA
/
TERAPIA POR MEDICAMENTOS
Ano de publicação:
2015
Tipo de documento:
Article