Opioid receptor agonists enhance the phosphorylation state of Fas-associated death domain (FADD) protein in the rat brain: functional interactions with casein kinase Ialpha, Galpha(i) proteins, and ERK1/2 signaling.
Opioid drugs have been proposed to promote anti-apoptotic signals in brain through inhibition of FADD protein [García-Fuster et al., 2007. Effects of opiate drugs on Fas-associated protein with death domain (FADD) and effector caspases in the rat brain: Regulation by the ERK1/2 MAP kinase pathway. Neuropsychopharmacology 32, 399-411]. FADD phosphorylation by casein kinase Ialpha (CKIalpha) appears to regulate its non-apoptotic activity. This study investigated the effects of opioids on p-FADD in rat brain, as well as various mechanisms that could link opioid receptors with p-FADD, including the modulation of CKIalpha, Galpha(i) proteins and ERK1/2 signaling. In rat, mouse and human brains, various anti-p-FADD antibodies immunodetected the monomeric and oligomeric forms of this protein, irrespective of the antibody origin and specific Ser191 or Ser194 phosphorylation site. Acute mu- and delta-agonists increased, through specific opioid receptor mechanisms, the content of oligomeric and monomeric p-FADD forms in rat cortical homogenates (25-61%) and subcellular compartments, with most relevant effects for sufentanil in membrane (239%) and nucleus (136%). p-FADD induction vanished with repeated (5days) morphine but not SNC-80, and opioid withdrawal induced a new (morphine) or sustained (SNC-80) stimulatory effect (32-33%). The kappa-agonist (-)-U-50488H failed to stimulate p-FADD. Sufentanil reduced CKI protein and kinase activity in the cytosol (30-37%). Morphine, but not SNC-80, augmented CKIalpha in cytosol, membrane and nucleus (36-104%). In contrast to FADD, the ability of SNC-80 to stimulate p-FADD was not sensitive to ERK1/2 blockade. Pertussis toxin did not prevent the opposite effects of SNC-80 on p-FADD and FADD because the toxin by itself markedly altered their basal contents, indicating that FADD could be a novel toxin target. The upregulation of p-FADD induced by mu/delta-agonists could play a relevant role in the anti-apoptotic and/or neuroplastic effects of opioids.
García-Fuster
M Julia
MJ
Institut Universitari d'Investigació en Ciències de la Salut, Universitat de les Illes Balears, E-07122 Palma de Mallorca, Spain.
Ramos-Miguel
Alfredo
A
Miralles
Antonio
A
García-Sevilla
Jesús A
JA
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D048128:Casein Kinase Ialpha / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008970:Molecular Weight; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D009292:Narcotic Antagonists; D009270:Naloxone; D048128:Casein Kinase Ialpha; D048052:Mitogen-Activated Protein Kinase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go