Choline promotes nicotinic receptor alpha4 + beta2 up-regulation.
Neuronal nicotinic acetylcholine receptors (nAChR) composed of alpha4 + beta2 subunits, the high affinity nicotine-binding site in the mammalian brain, up-regulate in response to chronic nicotine exposure. The identities of endogenous mediators of this process are unknown. We find that choline also up-regulates alpha4 + beta2 nAChRs stably expressed by HEK293 cells as measured by increased [(3)H]epibatidine density. Choline-mediated up-regulation is dose-dependent and corresponds with an increase in beta2 subunit protein expression. The choline kinase inhibitor hemicholinium-3 inhibits approximately 60% of choline-mediated up-regulation revealing both an HC3-dependent and -independent pathway. Furthermore, choline-mediated up-regulation is not additive with up-regulation agents such as nicotine, but it is additive with weaker promoters of the up-regulation process. When co-applied with the pro-inflammatory cytokine tumor necrosis factor alpha, choline-mediated up-regulation is increased further through a mechanism that includes an increase in both alpha4 and beta2 protein expression, and this is inhibited by the p38 MAPK inhibitor SB202190. These findings extend the view that up-regulation of alpha4 + beta2 nAChRs is a normal physiological response to altered metabolic and inflammatory conditions.
Gahring
Lorise C
LC
Salt Lake City Veterans Affairs-Geriatrics Research, Education, and Clinical Center, Salt Lake City, Utah, USA.
Vasquez-Opazo
Gustavo A
GA
Rogers
Scott W
SW
D001667:Binding, Competitive / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D002794:Choline / Q000494:pharmacology*; D002797:Choline Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006426:Hemicholinium 3 / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D007093:Imidazoles; D014179:Neurotransmitter Uptake Inhibitors; D018697:Nootropic Agents; D011725:Pyridines; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; C403531:nicotinic receptor alpha4beta2; D006426:Hemicholinium 3; D002797:Choline Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D002794:Choline; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole
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