title: Phosphocholine - an agonist of metabotropic but not of ionotropic functions of α9-containing nicotinic acetylcholine receptors.
abstract: We demonstrated previously that phosphocholine and phosphocholine-modified macromolecules efficiently inhibit ATP-dependent release of interleukin-1β from human and murine monocytes by a mechanism involving nicotinic acetylcholine receptors (nAChR). Interleukin-1β is a potent pro-inflammatory cytokine of innate immunity that plays pivotal roles in host defence. Control of interleukin-1β release is vital as excessively high systemic levels cause life threatening inflammatory diseases. In spite of its structural similarity to acetylcholine, there are no other reports on interactions of phosphocholine with nAChR. In this study, we demonstrate that phosphocholine inhibits ion-channel function of ATP receptor P2X7 in monocytic cells via nAChR containing α9 and α10 subunits. In stark contrast to choline, phosphocholine does not evoke ion current responses in Xenopus laevis oocytes, which heterologously express functional homomeric nAChR composed of α9 subunits or heteromeric receptors containing α9 and α10 subunits. Preincubation of these oocytes with phosphocholine, however, attenuated choline-induced ion current changes, suggesting that phosphocholine may act as a silent agonist. We conclude that phophocholine activates immuno-modulatory nAChR expressed by monocytes but does not stimulate canonical ionotropic receptor functions.
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, German Centre for Lung Research, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Richter
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, German Centre for Lung Research, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Mathes
authors.affiliation: Department of Physiology, University of Otago, Dunedin, New Zealand.
authors.forename: M
authors.initials: M
authors.lastname: Fronius
authors.affiliation: Institute for Animal Physiology, Justus-Liebig-University of Giessen, Giessen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Althaus
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, German Centre for Lung Research, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hecker
authors.affiliation: Intitute for Anatomy and Cell Biology, Julius-Maximilians-University of Wuerzburg, Wuerzburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Krasteva-Christ
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, German Centre for Lung Research, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Padberg
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Hone
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah, USA.|George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, Utah, USA.|Department of Psychiatry, University of Utah, Salt Lake City, Utah, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, German Centre for Lung Research, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Zakrzewicz
authors.affiliation: Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, German Centre for Lung Research, Justus-Liebig-University Giessen, Giessen, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Grau
mesh_terms: D000818:Animals; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D010767:Phosphorylcholine / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D020298:U937 Cells
chemical_list: C493739:CHRNA10 protein, human; C498540:CHRNA9 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; C546468:P2RX7 protein, human; D011978:Receptors, Nicotinic; D058486:Receptors, Purinergic P2X7; D010767:Phosphorylcholine