Upregulation of Nicotinic Acetylcholine Receptor alph4+beta2 through a Ligand-Independent PI3Kbeta Mechanism That Is Enhanced by TNFalpha and the Jak2/p38Mapk Pathways

Assembly of mature α4β2 nAChRs from a precursor pool of individual subunits can be upregulated by nicotine, possibly acting as a chaperone to increase α4+β2 subunit association and subcellular transport. The mechanisms through which choline and TNFα influence this process is to ultimately increase β2 subunit production (favoring pentameric α4+β2 assembly) through a p38MAPK mechanism that is inhibited by SB202190. The activity of p38MAPK is balanced by constitutive inhibition by PI3kβ (inhibited by PI828) and promoted by an increase in Jak2 kinase activity (inhibited by AG490). Jak2 activation is stimulated by choline acting through a choline kinase (CK) pathway that is distinguished by hemicholinium3-sensitivity (HC3) pathway or signaling by the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) acting through its receptor, TNFR1. The choline mediated upregulation mechanism through the HC3-insensitve pathway (CK-, in light grey) is not yet characterized but also produces upregulation through increased β2 production.

Publication

Upregulation of Nicotinic Acetylcholine Receptor alph4+beta2 through a Ligand-Independent PI3Kbeta Mechanism That Is Enhanced by TNFalpha and the Jak2/p38Mapk Pathways. (2015) Scott W. Rogers, et al. PLoS One. 2015;10(11):e0143319. Figure: F8. All organisms Homo sapiens Mus musculus Rattus norvegicus Drosophila melanogaster

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