Abstract
Neuronal nicotinic acetylcholine receptors (nAChR) composed of α4 + β2 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 α4 + β2 nAChRs stably expressed by HEK293 cells as measured by increased [3H]epibatidine density. Choline-mediated up-regulation is dose-dependent and corresponds with an increase in β2 subunit protein expression. The choline kinase inhibitor hemicholinium-3 inhibits ∼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 α, choline-mediated up-regulation is increased further through a mechanism that includes an increase in both α4 and β2 protein expression, and this is inhibited by the p38 MAPK inhibitor SB202190. These findings extend the view that up-regulation of α4 + β2 nAChRs is a normal physiological response to altered metabolic and inflammatory conditions.
Highlights
Neuronal nicotinic acetylcholine receptors composed of ␣4 ؉ 2 subunits, the high affinity nicotine-binding site in the mammalian brain, up-regulate in response to chronic nicotine exposure
Choline Modifies nicotinic acetylcholine receptors (nAChR) Expression Consistent with Upregulation—Because receptor subunit composition corresponds with the magnitude of up-regulation as measured by an increase in [3H]EB-binding site density, the impact of choline treatment on this process for four different nAChR receptor subtypes expressed stably by independent 293 cell lines was measured after exposure to 500 M choline for 24 h
Up-regulation of high affinity nicotine-binding sites in response to receptor ligands such as nicotine was reported over 20 years ago in studies of rodents receiving chronic nicotine (38, 39)
Summary
Neuronal nicotinic acetylcholine receptors (nAChR) composed of ␣4 ؉ 2 subunits, the high affinity nicotine-binding site in the mammalian brain, up-regulate in response to chronic nicotine exposure. We find that choline up-regulates ␣4 ؉ 2 nAChRs stably expressed by HEK293 cells as measured by increased [3H]epibatidine density. Choline-mediated up-regulation is dose-dependent and corresponds with an increase in 2 subunit protein expression.
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