title: Tumor necrosis factor alpha enhances nicotinic receptor up-regulation via a p38MAPK-dependent pathway.
abstract: A response by key neuronal nicotinic acetylcholine receptors (nAChRs) to sustained nicotine exposure is up-regulation. Although this unusual receptor characteristic contributes to processes ranging from aging to addiction, the normal physiologic reason for this response is unknown. We find that up-regulation of [(3)H]epibatidine binding and function in HEK293 cells stably expressing alpha4beta2-nAChR is significantly enhanced by co-application of the proinflammatory cytokine, tumor necrosis factor alpha. The mechanism of tumor necrosis factor alpha-enhanced up-regulation requires transcription, new protein synthesis, and signaling through p38(MAPK) as demonstrated by complete inhibition using SB 202190. This finding extends the possibilities for nAChR-inflammatory interactions in normal physiological processes and offers novel insights into endogenous mechanisms that can modify up-regulation.
authors.affiliation: Salt Lake City Veterans Affairs-Geriatrics Research, Education, Clinical Center, Salt Lake City, Utah 84148, USA. Lorise.Gahring@hsc.utah.edu
authors.forename: Lorise C
authors.initials: LC
authors.lastname: Gahring
authors.forename: Amber V
authors.initials: AV
authors.lastname: Osborne-Hereford
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Vasquez-Opazo
authors.forename: Scott W
authors.initials: SW
authors.lastname: Rogers
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000196:embryology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D009538:Nicotine; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C082748:epibatidine