title: Nitric Oxide-GAPDH Transcriptional Signaling Mediates Behavioral Actions of Cocaine.
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.
authors.forename: Maged M
authors.initials: MM
authors.lastname: Harraz
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ssnyder@jhmi.edu.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010082:Oxepins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000098563:Seven in Absentia Proteins
chemical_list: D018765:Dopamine Uptake Inhibitors; D009687:Nuclear Proteins; D010082:Oxepins; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine; D009569:Nitric Oxide; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D003042:Cocaine