Tumor necrosis factor alpha enhances nicotinic receptor up-regulation via a p38MAPK-dependent pathway.
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.
Gahring
Lorise C
LC
Salt Lake City Veterans Affairs-Geriatrics Research, Education, Clinical Center, Salt Lake City, Utah 84148, USA. Lorise.Gahring@hsc.utah.edu
Osborne-Hereford
Amber V
AV
Vasquez-Opazo
Gustavo A
GA
Rogers
Scott W
SW
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*
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