TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Zakrzewicz, Anna
A1  - Richter, Katrin
A1  - Agne, Alisa
A1  - Wilker, Sigrid
A1  - Siebers, Kathrin
A1  - Fink, Bijan
A1  - Krasteva-Christ, Gabriela
A1  - Althaus, Mike
A1  - Padberg, Winfried
A1  - Hone, Arik J.
A1  - McIntosh, J. Michael
A1  - Grau, Veronika
T1  - 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
JF  - Frontiers in Cellular Neuroscience
N2  - 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.
KW  - glycerophosphocholine
KW  - nicotine and phosphocholine
KW  - CHRNA
KW  - lysophosphatidylcholine
KW  - inflammasome
KW  - acetylcholine
KW  - interleukin-1beta
SN  - 1662-5102
SS  - 1662-5102
U6  - https://doi.org/10.3389/fncel.2017.00189
DO  - https://doi.org/10.3389/fncel.2017.00189
PM  - 28725182
VL  - 11
PB  - Frontiers Media
ER  -