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Canonical and Novel Non-Canonical Cholinergic Agonists Inhibit ATP-Induced Release of Monocytic Interleukin-1 beta via Different Combinations of Nicotinic Acetylcholine Receptor Subunits alpha 7, alpha 9 and alpha 10

  • Recently, we discovered a cholinergic mechanism that inhibits the adenosine triphosphate (ATP)-dependent release of interleukin-1 beta (IL-1 beta) by human monocytes via nicotinic acetylcholine receptors (nAChRs) composed of alpha 7, alpha 9 and/or alpha 10 subunits. Furthermore, we identified phosphocholine (PC) and dipalmitoylphosphatidylcholine (DPPC) as novel nicotinic agonists that elicit metabotropic activity at monocytic nAChR. Interestingly, PC does not provoke ion channel responses at conventional nAChRs composed of subunits alpha 9 and alpha 10. The purpose of this study is to determine the composition of nAChRs necessary for nicotinic signaling in monocytic cells and to test the hypothesis that common metabolites of phosphatidylcholines, lysophosphatidylcholine (LPC) and glycerophosphocholine (G-PC), function as nAChR agonists. In peripheral blood mononuclear cells from nAChR gene-deficient mice, we demonstrated that inhibition of ATP-dependent release of IL-1 beta by acetylcholine (ACh), nicotine and PC depends on subunits alpha 7, alpha 9 and alpha 10. Using a panel of nAChR antagonists and siRNA technology, we confirmed the involvement of these subunits in the control of IL-1 beta release in the human monocytic cell line U937. Furthermore, we showed that LPC (C16:0) and G-PC efficiently inhibit ATP-dependent release of IL-1 beta. Of note, the inhibitory effects mediated by LPC and G-PC depend on nAChR subunits alpha 9 and alpha 10, but only to a small degree on alpha 7. In Xenopus laevis oocytes heterologously expressing different combinations of human alpha 7, alpha 9 or alpha 10 subunits, ACh induced canonical ion channel activity, whereas LPC, G-PC and PC did not. In conclusion, we demonstrate that canonical nicotinic agonists and PC elicit metabotropic nAChR activity in monocytes via interaction of nAChR subunits alpha 7, alpha 9 and alpha 10. For the metabotropic signaling of LPC and G-PC, nAChR subunits alpha 9 and alpha 10 are needed, whereas alpha 7 is virtually dispensable. Furthermore, molecules bearing a PC group in general seem to regulate immune functions without perturbing canonical ion channel functions of nAChR.

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Document Type:Article
Author:Anna Zakrzewicz, Katrin Richter, Alisa Agne, Sigrid Wilker, Kathrin Siebers, Bijan Fink, Gabriela Krasteva-Christ, Mike Althaus, Winfried Padberg, Arik J. Hone, J. Michael McIntosh, Veronika Grau
Parent Title (English):Frontiers in Cellular Neuroscience
Article Number:189
Publisher:Frontiers Media
Date of first publication:2017/07/05
Funding:This study was supported by the LOEWE Program of the State of Hessen (Non-neuronal cholinergic systems) to VG, research grant from the German Research Foundation to VG (GR 1094/7-1). GK-C received funding by SFB TR84. JMM received funding from NIH Grants P01-GM48677 and R01-GM103801
Keyword:CHRNA; acetylcholine; glycerophosphocholine; inflammasome; interleukin-1beta; lysophosphatidylcholine; nicotine and phosphocholine
Departments, institutes and facilities:Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Entry in this database:2023/03/22