Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System

Abstract

Cholines acylated with unsaturated fatty acids are a recently discovered family of endogenous lipids. However, the data on the biological activity of acylcholines remain very limited. We hypothesized that acylcholines containing residues of arachidonic (AA-CHOL), oleic (Ol-CHOL), linoleic (Ln-CHOL), and docosahexaenoic (DHA-CHOL) acids act as modulators of the acetylcholine signaling system. In the radioligand binding assay, acylcholines showed inhibition in the micromolar range of both α7 neuronal nAChR overexpressed in GH4C1 cells and muscle type nAChR from Torpedo californica, as well as Lymnaea stagnalis acetylcholine binding protein. Functional response was checked in two cell lines endogenously expressing α7 nAChR. In SH-SY5Y cells, these compounds did not induce Ca2+ rise, but inhibited the acetylcholine-evoked Ca2+ rise with IC50 9 to 12 μM. In the A549 lung cancer cells, where α7 nAChR activation stimulates proliferation, Ol-CHOL, Ln-CHOL, and AA-CHOL dose-dependently decreased cell viability by up to 45%. AA-CHOL inhibited human erythrocyte acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) by a mixed type mechanism with Ki = 16.7 ± 1.5 μM and αKi = 51.4 ± 4.1 μM for AChE and Ki = 70.5 ± 6.3 μM and αKi = 214 ± 17 μM for BChE, being a weak substrate of the last enzyme only, agrees with molecular docking results. Thus, long-chain unsaturated acylcholines could be viewed as endogenous modulators of the acetylcholine signaling system.

Multi-Omic Analyses Reveal Bifidogenic Effect and Metabolomic Shifts in Healthy Human Cohort Supplemented With a Prebiotic Dietary Fiber Blend

“…Long-chain acylcholines have been found to have associations with a number of disease states (115), including elevated concentrations in endometrial cancer patients (116) and patients at high risk of pulmonary embolism (117), and lower concentrations in patients with myalgic encephalomyelitis/chronic fatigue syndrome (118) and chronic thromboembolic pulmonary hypertension (119). Acylcholines are known to have cholinergic signaling properties, with important implications for signaling through the nicotinic acetylcholine receptor (α7 nAChR), and effects on cytokine synthesis in macrophages and T cells (115,120).…”

Nicotinic acetylcholine receptors regulate clustering, fusion and acidification of the rat brain synaptic vesicles

“…Our unpublished data allow suggesting that phosphocholine also affects α7 nAChRs. Recently published evidence demonstrates that long-chain unsaturated acylcholines can be viewed as endogenous modulators of α7 nAChRs (Akimov et al, 2020) These choline derivatives are natural components of membrane lipids, which, similarly to α7 nAChRs agonists, can affect SVs fusion with the PM and the process of neurotransmitter release. In contrast to fusion, which was affected similarly by nicotine and PNU282987 activating both α4β2 and α7(β2) nAChRs, SVs acidification was affected by nicotine only suggesting that α7 nAChRs are not involved in regulating the proton flux (i.e.…”

Development of Chrysin Loaded Oil-in-Water Nanoemulsion for Improving Bioaccessibility

“…Interestingly, Figure 2C displays that solubilized chrysin-NE inhibited BChE more than pure chrysin. It could be possible that medium chain fatty acids and chrysin may have a combined inhibitory effect on BChE [33]. Data showed that chrysin exhibited biological activities in vitro, even after nanoemulsion development.…”