Phosphocholine – an agonist of metabotropic but not of ionotropic functions of α9-containing nicotinic acetylcholine receptors

Richter, Katrin; Mathes, Verena; Fronius, Martin; Althaus, Mike; Hecker, Andreas; Krasteva‐Christ, Gabriela; Padberg, Winfried; Hone, Arik J.; McIntosh, J. Michael; Zakrzewicz, Anna; Grau, Veronika

doi:10.1038/srep28660

Cited by 78 publications

(195 citation statements)

References 47 publications

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“…These results are in line with the idea that chemokine signaling triggers a recently described mechanism involving activation of metabotropic functions of noncanonical nAChR containing subunits α 7 and α 9 that inhibit P2X7 signaling and, consequently, BzATP-induced release of IL-1 β [18, 20]. Of note, the inhibitory effect of acetylcholine (10 μ M) was not impaired by silencing of CCR expression (Figure 3(c)), suggesting that nAChR are acting downstream of CCR.…”

Section: Resultssupporting

confidence: 88%

Chemokines (CCL3, CCL4, and CCL5) Inhibit ATP-Induced Release of IL-1β by Monocytic Cells

Amati

Zakrzewicz

Siebers

et al. 2017

Mediators of Inflammation

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Chemokines and ATP are among the mediators of inflammatory sites that can enter the circulation via damaged blood vessels. The main function of chemokines is leukocyte mobilization, and ATP typically triggers inflammasome assembly. IL-1β, a potent inflammasome-dependent cytokine of innate immunity, is essential for pathogen defense. However, excessive IL-1β may cause life-threatening systemic inflammation. Here, we hypothesize that chemokines control ATP-dependent secretion of monocytic IL-1β. Lipopolysaccharide-primed human monocytic U937 cells were stimulated with the P2X7 agonist BzATP for 30 min to induce IL-1β release. CCL3, CCL4, and CCL5 dose dependently inhibited BzATP-stimulated release of IL-1β, whereas CXCL16 was ineffective. The effect of CCL3 was confirmed for primary mononuclear leukocytes. It was blunted after silencing CCR1 or calcium-independent phospholipase A2 (iPLA2) by siRNA and was sensitive to antagonists of nicotinic acetylcholine receptors containing subunits α7 and α9. U937 cells secreted small factors in response to CCL3 that mediated the inhibition of IL-1β release. We suggest that CCL chemokines inhibit ATP-induced release of IL-1β from U937 cells by a triple-membrane-passing mechanism involving CCR, iPLA2, release of small mediators, and nicotinic acetylcholine receptor subunits α7 and α9. We speculate that whenever chemokines and ATP enter the circulation concomitantly, systemic release of IL-1β is minimized.

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Section: Resultssupporting

confidence: 88%

Chemokines (CCL3, CCL4, and CCL5) Inhibit ATP-Induced Release of IL-1β by Monocytic Cells

Amati

Zakrzewicz

Siebers

et al. 2017

Mediators of Inflammation

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“…In our study the acute inhibition of M2R in the trachea almost doubled the increase in PTS after stimulation of brush cells with bitter tasting substances. 14,51,52 In conclusion, the present findings reveal that the whole transcriptome of tracheal epithelial BC is distinct to that | 331 HOLLENHORST ET aL. 16 Additionally, ACh mediates important innate immune functions after being released from BC, for example, induction of protective respiratory reflexes.…”

mentioning

confidence: 68%

Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling

et al. 2019

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractFor protection from inhaled pathogens many strategies have evolved in the airways such as mucociliary clearance and cough. We have previously shown that protective respiratory reflexes to locally released bacterial bitter "taste" substances are most probably initiated by tracheal brush cells (BC). Our single-cell RNA-seq analysis of murine BC revealed high expression levels of cholinergic and bitter taste signaling transcripts (Tas2r108, Gnat3, Trpm5). We directly demonstrate the secretion of acetylcholine (ACh) from BC upon stimulation with the Tas2R agonist denatonium. Inhibition of the taste transduction cascade abolished the increase in [Ca 2+ ] i in | 317 HOLLENHORST ET aL.

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“…The α9 and α10 subunit transcripts have been identified in immune cells, including lymphocytes, neutrophils, and monocytes (36). It has also recently been shown that functional α9α10 nAChRs regulate ATP-dependent cytokine release in monocytes (37) and that α9-containing nAChRs modify the function of proinflammatory monocytes (38). The α9-containing nAChRs also modulate the influx of monocytes and neutrophils in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis (39,40).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

Romero

Christensen

Mannelli

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

146

204

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Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioid mechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABA B receptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABA B receptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapyinduced neuropathic pain.pain | chemotherapy | alpha9 | nicotinic

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Phosphocholine – an agonist of metabotropic but not of ionotropic functions of α9-containing nicotinic acetylcholine receptors

Cited by 78 publications

References 47 publications

Chemokines (CCL3, CCL4, and CCL5) Inhibit ATP-Induced Release of IL-1β by Monocytic Cells

Chemokines (CCL3, CCL4, and CCL5) Inhibit ATP-Induced Release of IL-1β by Monocytic Cells

Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling

Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

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