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Science Immunology Mar 2022The gallbladder stores bile between meals and empties into the duodenum upon demand and is thereby exposed to the intestinal microbiome. This exposure raises the need...
The gallbladder stores bile between meals and empties into the duodenum upon demand and is thereby exposed to the intestinal microbiome. This exposure raises the need for antimicrobial factors, among them, mucins produced by cholangiocytes, the dominant epithelial cell type in the gallbladder. The role of the much less frequent biliary tuft cells is still unknown. We here show that propionate, a major metabolite of intestinal bacteria, activates tuft cells via the short-chain free fatty acid receptor 2 and downstream signaling involving the cation channel transient receptor potential cation channel subfamily M member 5. This results in corelease of acetylcholine and cysteinyl leukotrienes from tuft cells and evokes synergistic paracrine effects upon the epithelium and the gallbladder smooth muscle, respectively. Acetylcholine triggers mucin release from cholangiocytes, an epithelial defense mechanism, through the muscarinic acetylcholine receptor M3. Cysteinyl leukotrienes cause gallbladder contraction through their cognate receptor CysLTR1, prompting emptying and closing. Our results establish gallbladder tuft cells as sensors of the microbial metabolite propionate, initiating dichotomous innate defense mechanisms through simultaneous release of acetylcholine and cysteinyl leukotrienes.
Topics: Acetylcholine; Epithelial Cells; Leukotrienes; Propionates
PubMed: 35245090
DOI: 10.1126/sciimmunol.abf6734 -
Allergology International : Official... Oct 2018Inhaled bronchodilator treatment with a long acting muscarinic antagonist (LAMA) reduces symptoms and the risk of exacerbations in COPD and asthma. However, increasing... (Review)
Review
Inhaled bronchodilator treatment with a long acting muscarinic antagonist (LAMA) reduces symptoms and the risk of exacerbations in COPD and asthma. However, increasing evidence from cell culture and animal studies suggests that anti-muscarinic drugs could also possess anti-inflammatory effects. Recent studies have revealed that acetylcholine (ACh) can be synthesized and released from both neuronal and non-neuronal cells, and the released ACh can potentiate airway inflammation and remodeling in airway diseases. However, these anti-inflammatory effects of anti-muscarinic drugs have not yet been confirmed in COPD and asthma patients. This review will focus on recent findings about the possible involvement of ACh in airway inflammation and remodeling, and the anti-inflammatory effect of anti-muscarinic drugs in airway diseases. Clarifying the acetylcholine-mediated inflammation could provide insights into the mechanisms of airway diseases, which could lead to future therapeutic strategies for inhibiting the disease progression and exacerbations.
Topics: Acetylcholine; Animals; Humans; Inflammation; Muscarinic Antagonists; Respiratory System; Respiratory Tract Diseases
PubMed: 29605098
DOI: 10.1016/j.alit.2018.02.008 -
Frontiers in Neural Circuits 2019The neocortex is densely innervated by basal forebrain (BF) cholinergic neurons. Long-range axons of cholinergic neurons regulate higher-order cognitive function and... (Review)
Review
The neocortex is densely innervated by basal forebrain (BF) cholinergic neurons. Long-range axons of cholinergic neurons regulate higher-order cognitive function and dysfunction in the neocortex by releasing acetylcholine (ACh). ACh release dynamically reconfigures neocortical microcircuitry through differential spatiotemporal actions on cell-types and their synaptic connections. At the cellular level, ACh release controls neuronal excitability and firing rate, by hyperpolarizing or depolarizing target neurons. At the synaptic level, ACh impacts transmission dynamics not only by altering the presynaptic probability of release, but also the magnitude of the postsynaptic response. Despite the crucial role of ACh release in physiology and pathophysiology, a comprehensive understanding of the way it regulates the activity of diverse neocortical cell-types and synaptic connections has remained elusive. This review aims to summarize the state-of-the-art anatomical and physiological data to develop a functional map of the cellular, synaptic and microcircuit effects of ACh in the neocortex of rodents and non-human primates, and to serve as a quantitative reference for those intending to build data-driven computational models on the role of ACh in governing brain states.
Topics: Acetylcholine; Animals; Computer Simulation; Models, Neurological; Neocortex; Synaptic Transmission
PubMed: 31031601
DOI: 10.3389/fncir.2019.00024 -
BMC Oral Health May 2022Sex hormones influence circulation, periodontitis, and wound healing. The aim of the study was to compare the endothelium-dependent and independent vasodilation in human...
BACKGROUND
Sex hormones influence circulation, periodontitis, and wound healing. The aim of the study was to compare the endothelium-dependent and independent vasodilation in human gingiva in men and women.
METHODS
Gingival blood flow was evaluated in twelve male and twelve female subjects with healthy gingiva and no systemic conditions after acetylcholine or nitric oxide donor (NitroPOHL). Agonists were administered into the gingival sulcus at the right secondary incisor (test site). Regional gingival blood flow (GBF) was imaged by Laser Speckle Contrast Imager from the marginal gingiva to the mucogingival junction in four consecutive regions (coronal, midway1, midway2 and apical). Blood flow was expressed in Laser Speckle Perfusion Unit (LSPU). The absolute maximal blood flow change (Dmax), the area under the blood flow curve (AUC), and the time to peak (TTP) were calculated.
RESULTS
Males had higher baseline GBF than females (257 ± 18.2 vs. 225 ± 18.8 LSPU, p < 0.001). Acetylcholine and NitroPOHL significantly increased the GBF in all test regions. The Dmax after the acetylcholine was reduced apically compared to the coronal (90 ± 13 LSPU vs. 117 ± 7 LSPU, p < 0.01), but it was similar after NitroPOHL (78 ± 9 LSPU vs. 86 ± 6 LSPU, p = 0.398) in both sexes. The Dmax and AUC were higher, and the TTP was smaller in men in most regions after acetylcholine but not after NitroPOHL.
CONCLUSION
In the human gingiva, the endothelium-independent vasodilation propagates without attenuation in the line of the vascular supply in both sexes. At the same time, the endothelium-dependent ascending vasodilation attenuates similarly in men and women. However, men had more pronounced endothelium-dependent vasodilation than women. Therefore, it might contribute to the increased severity of periodontal disease in men.
TRIAL REGISTRATION
The study was registered with ClinicalTrials.gov on 09.06.2021 (NCT04918563).
Topics: Acetylcholine; Endothelium; Female; Gingiva; Humans; Male; Regional Blood Flow; Vasodilation
PubMed: 35562729
DOI: 10.1186/s12903-022-02186-2 -
Progress in Neurobiology Apr 2015Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from... (Review)
Review
Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestation of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia.
Topics: Acetylcholine; Animals; Corpus Striatum; Dystonic Disorders; Humans; Interneurons
PubMed: 25697043
DOI: 10.1016/j.pneurobio.2015.02.002 -
Philosophical Transactions of the Royal... Jun 2018The concept of allosteric interaction was initially proposed to account for the inhibitory feedback mechanism mediated by bacterial regulatory enzymes. In contrast with... (Review)
Review
The concept of allosteric interaction was initially proposed to account for the inhibitory feedback mechanism mediated by bacterial regulatory enzymes. In contrast with the classical mechanism of competitive, steric, interaction between ligands for a common site, allosteric interactions take place between topographically distinct sites and are mediated by a discrete and reversible conformational change of the protein. The concept was soon extended to membrane receptors for neurotransmitters and shown to apply to the signal transduction process which, in the case of the acetylcholine nicotinic receptor (nAChR), links the ACh binding site to the ion channel. Pharmacological effectors, referred to as allosteric modulators, such as Ca ions and ivermectin, were discovered that enhance the transduction process when they bind to sites distinct from the orthosteric ACh site and the ion channel. The recent X-ray and electron microscopy structures, at atomic resolution, of the resting and active conformations of several homologues of the nAChR, in combination with atomistic molecular dynamics simulations reveal a stepwise quaternary transition in the transduction process with tertiary changes modifying the boundaries between subunits. These interfaces host orthosteric and allosteric modulatory sites which structural organization changes in the course of the transition. The nAChR appears as a typical allosteric machine. The model emerging from these studies has led to the conception and development of several new pharmacological agents.This article is part of a discussion meeting issue 'Allostery and molecular machines'.
Topics: Acetylcholine; Animals; Binding Sites; Humans; Ligands; Molecular Dynamics Simulation; Receptors, Nicotinic
PubMed: 29735728
DOI: 10.1098/rstb.2017.0174 -
Annual International Conference of the... Jul 2019Acetylcholine is a neurotransmitter and a neuromodulator found in the autonomic, peripheral and central nervous systems. Diazinon is a pesticide with toxic effects on...
Acetylcholine is a neurotransmitter and a neuromodulator found in the autonomic, peripheral and central nervous systems. Diazinon is a pesticide with toxic effects on humans, such as the inhibition of acetylcholine. In this paper, a biosensor is proposed for the detection of acetylcholine (range 70 - 1000 μM) and diazinon (range 0.3 - 20000 ppb). This biosensor combines a pH-sensitive layer of reduced graphene oxide functionalized with 4-aminobenzoic acid and acetylcholinesterase. This enzyme was immobilized on reduced graphene oxide and it catalyzed the conversion of acetylcholine into choline and acetic acid, locally decreasing the pH value and triggering the sensor response. The limit of detection for the acetylcholine and diazinon were 70 μM and 0.3 ppb, respectively.
Topics: Acetylcholine; Biosensing Techniques; Diazinon; Electrodes; Enzymes, Immobilized; Humans
PubMed: 31946099
DOI: 10.1109/EMBC.2019.8856959 -
Journal of Cardiology Jan 2017The spasm provocation tests of ergonovine and acetylcholine have been employed in the cardiac catheterization laboratory. Ergonovine acts through the serotogenic... (Review)
Review
The spasm provocation tests of ergonovine and acetylcholine have been employed in the cardiac catheterization laboratory. Ergonovine acts through the serotogenic receptors, while acetylcholine acts through the muscarinic cholinergic receptors. Different mediators may have the potential to cause different coronary responses. However, there are few reports concerning the coronary response between ergonovine and acetylcholine in the same patients. Acetylcholine is supersensitive for females; spasm provoked by ergonovine is focal and proximal, whereas provoked spasm by acetylcholine is diffuse and distal. We should use both tests as supplementary in the clinic because ergonovine and acetylcholine have self-limitations to induce coronary spasms during daily life. The maximal pharmacological doses, administration methods, and the angiographical positive definition are remarkably different for each institution in the world. We recommend the pharmacological spasm provocation tests as Class I in the guidelines in patients with vasospastic angina throughout the world.
Topics: Acetylcholine; Cardiovascular Agents; Coronary Vasospasm; Ergonovine; Female; Heart; Heart Function Tests; Humans; Male; Spasm
PubMed: 27856130
DOI: 10.1016/j.jjcc.2016.09.012 -
Neurobiology of Learning and Memory Apr 2016In addition to the neuromodulatory role of cholinergic systems, brief, temporally discrete cholinergic release events, or "transients", have been associated with the... (Review)
Review
In addition to the neuromodulatory role of cholinergic systems, brief, temporally discrete cholinergic release events, or "transients", have been associated with the detection of cues in attention tasks. Here we review four main findings about cholinergic transients during cognitive processing. Cholinergic transients are: (1) associated with the detection of a cue and influenced by cognitive state; (2) not dependent on reward outcome, although the timing of the transient peak co-varies with the temporal relationship between detection and reward delivery; (3) correlated with the mobilization of the cue-evoked response; (4) causal mediators of shifts from monitoring to cue detection. We next discuss some of the key questions concerning the timing and occurrence of transients within the framework of available evidence including: (1) Why does the shift from monitoring to cue detection require a transient? (2) What determines whether a cholinergic transient will be generated? (3) How can cognitive state influence transient occurrence? (4) Why do cholinergic transients peak at around the time of reward delivery? (5) Is there evidence of cholinergic transients in humans? We conclude by outlining future research studies necessary to more fully understand the role of cholinergic transients in mediating cue detection.
Topics: Acetylcholine; Animals; Attention; Brain; Cholinergic Neurons; Cognition; Cues; Humans; Reward
PubMed: 26911787
DOI: 10.1016/j.nlm.2016.02.008 -
Journal of Pharmacological and... 2023The central nervous system of hard ticks (Ixodidae) consists of a concentrated merged nerve mass known as the synganglion. Although knowledge of tick neurobiology has...
The central nervous system of hard ticks (Ixodidae) consists of a concentrated merged nerve mass known as the synganglion. Although knowledge of tick neurobiology has dramatically improved over the last two decades, this is the first time that isolation and electrophysiological recordings have been carried out on tick neurons from the synganglion. Method: We developed a simple protocol for synganglion neuron isolation and used a whole-cell patch clamp to measure ionic currents induced by acetylcholine, nicotine and muscarine. Relatively large neurons (∼ 25 μm and ∼ 35 μm) were isolated and 1 mM acetylcholine was used to induce strong inward currents of -0.38 ± 0.1 nA and - 1.04 ± 0.1 nA, respectively, with the corresponding cell capacitances being at around 142 pF and 188 pF. In addition, successive application of 1 mM acetylcholine through ∼25 μm and ∼ 35 μm cells for increasing amounts of time resulted in a rapid reduction in current amplitudes. We also found that acetylcholine-evoked currents were associated with a reversible increase in intracellular calcium levels for each neuronal type. In contrast, 1 mM muscarine and nicotine induced a strong and non-reversible increase in intracellular calcium levels. This study serves as a proof of concept for the mechanical isolation of tick synganglion neurons followed by their electrophysiological recording. This approach will aid investigations into the pharmacological properties of tick neurons and provides the tools needed for the identification of drug-targeted sites and effective tick control measures.
Topics: Animals; Ixodes; Nicotine; Acetylcholine; Calcium; Muscarine; Neurons
PubMed: 37866797
DOI: 10.1016/j.vascn.2023.107473