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ACS Nano Jun 2018A suite of imaging tools for detecting specific chemicals in the central nervous system could accelerate the understanding of neural signaling events critical to brain...
A suite of imaging tools for detecting specific chemicals in the central nervous system could accelerate the understanding of neural signaling events critical to brain function and disease. Here, we introduce a class of nanoparticle sensors for the highly specific detection of acetylcholine in the living brain using magnetic resonance imaging. The nanosensor is composed of acetylcholine-catalyzing enzymes and pH-sensitive gadolinium contrast agents co-localized onto the surface of polymer nanoparticles, which leads to changes in T relaxation rate (1/ T). The mechanism of the sensor involves the enzymatic hydrolysis of acetylcholine leading to a localized decrease in pH which is detected by the pH-sensitive gadolinium chelate. The concomitant change in 1/ T in vitro measured a 20% increase from 0 to 10 μM acetylcholine concentration. The applicability of the nanosensors in vivo was demonstrated in the rat medial prefrontal cortex showing distinct changes in 1/ T induced by pharmacological stimuli. The highly specific acetylcholine nanosensor we present here offers a promising strategy for detection of cholinergic neurotransmission and will facilitate our understanding of brain function through chemical imaging.
Topics: Acetylcholine; Animals; Brain; Contrast Media; Gadolinium; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Male; Models, Molecular; Molecular Imaging; Molecular Structure; Nanoparticles; Particle Size; Polymers; Rats; Rats, Sprague-Dawley; Surface Properties
PubMed: 29851460
DOI: 10.1021/acsnano.8b01640 -
International Journal of Molecular... Apr 2023Unexpectedly, the affinity of the seven-transmembrane muscarinic acetylcholine receptors for their agonists is modulated by membrane depolarization. Recent reports...
Unexpectedly, the affinity of the seven-transmembrane muscarinic acetylcholine receptors for their agonists is modulated by membrane depolarization. Recent reports attribute this characteristic to an embedded charge movement in the muscarinic receptor, acting as a voltage sensor. However, this explanation is inconsistent with the results of experiments measuring acetylcholine binding to muscarinic receptors in brain synaptoneurosomes. According to these results, the gating of the voltage-dependent sodium channel (VDSC) acts as the voltage sensor, generating activation of Go-proteins in response to membrane depolarization, and this modulates the affinity of muscarinic receptors for their cholinergic agonists.
Topics: Acetylcholine; Membrane Potentials; Receptors, Muscarinic; Cholinergic Agonists; Sodium Channels
PubMed: 37108699
DOI: 10.3390/ijms24087538 -
Japanese Journal of Pharmacology Jan 2001Acetylcholine (ACh) is a well characterized neurotransmitter occurring throughout the animal kingdom. In addition, both muscarinic and nicotinic ACh receptors have been... (Review)
Review
Acetylcholine (ACh) is a well characterized neurotransmitter occurring throughout the animal kingdom. In addition, both muscarinic and nicotinic ACh receptors have been identified on lymphocytes of various origin, and their stimulation by muscarinic or nicotinic agonists elicits a variety of functional and biochemical effects. It was thus initially postulated that the parasympathetic nervous system may play a role in modulating immune system function. However, ACh in the blood has now been localized to lymphocytes; indeed expression of choline acetyltransferase (ChAT), an ACh synthesizing enzyme, has been shown in human blood mononuclear leukocytes, human leukemic T-cell lines and rat lymphocytes. Stimulation of T-lymphocytes with phytohemagglutinin activates the lymphoid cholinergic system, as evidenced by increased synthesis and release of ACh and increased expression of mRNAs encoding ChAT and ACh receptors. The observation that M3 muscarinic receptor stimulation by ACh and other agonists increases the intracellular free Ca2+ concentration and upregulates c-fos gene expression strongly argues that ACh, synthesized and released from T-lymphocytes, acts as an autocrine and/or paracrine factor regulating immune function. These findings present a compelling picture in which immune function is, at least in part, under the control of an independent lymphoid cholinergic system.
Topics: Acetylcholine; Animals; Calcium; Choline O-Acetyltransferase; Cholinergic Agonists; Gene Expression; Humans; Lymphocytes; RNA, Messenger; Receptors, Cholinergic
PubMed: 11243565
DOI: 10.1254/jjp.85.11 -
Anesthesiology Jul 1996Acetylcholine causes synthesis of nitric oxide in vascular endothelium, and presumptive evidence in vivo suggests spinally released acetylcholine causes antinociception...
BACKGROUND
Acetylcholine causes synthesis of nitric oxide in vascular endothelium, and presumptive evidence in vivo suggests spinally released acetylcholine causes antinociception and increased sympathetic nervous system activity via a nitric oxide mechanism. The purpose of this study was to determine, using a recently described bioassay system, whether acetylcholine stimulates nitric oxide release from spinal cord tissue in vitro.
METHODS
Rat thoracolumbar spinal cord slices were incubated in a tissue chamber and perfused with Krebs-Henseleit solution. The perfusate was then passed through endotheliumdenuded rat aortic rings and their tension was measured. Vascular rings were preconstricted with phenylephrine, then were exposed to spinal cord perfusate with increasing concentrations (10(-12)-10(-4)M) of acetylcholine alone or with various antagonists.
RESULTS
Acetylcholine perfusion of spinal tissue caused concentration-dependent relaxations of the aortic rings, an effect blocked by each of the muscarinic antagonists, atropine, pirenzepine, and AFDX-116. Acetylcholine-induced relaxation also was antagonized by an inhibitor of nitric oxide synthase (N-methyl-L-arginine), a nitric oxide scavenger (hemoglobin) and an inhibitor of guanylate cyclase (methylene blue).
CONCLUSIONS
These results demonstrate release of a vasorelaxant from spinal cord tissue by acetylcholine, which results from an action on muscarinic receptors and exhibits a pharmacology consistent with nitric oxide. Although precise anatomic localization of acetylcholine's action is not possible with this system, these results add to evidence that acetylcholine causes nitric oxide synthesis in the spinal cord.
Topics: Acetylcholine; Animals; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley; Spinal Cord; Vasodilation
PubMed: 8694354
DOI: 10.1097/00000542-199607000-00015 -
American Journal of Physiology.... Sep 2010Fatty acids, acetylcholine, and GLP-1 enhance insulin secretion in a glucose-dependent manner. However, the interplay between glucose, fatty acids, and the...
Fatty acids, acetylcholine, and GLP-1 enhance insulin secretion in a glucose-dependent manner. However, the interplay between glucose, fatty acids, and the neuroendocrine regulators of insulin secretion is not well understood. Therefore, we studied the acute effects of PA (alone or in combination with glucose, acetylcholine, or GLP-1) on isolated cultured mouse islets. Two different sets of experiments were designed. In one, a fixed concentration of 0.5 mM of PA bound to 0.15 mM BSA was used; in the other, a PA ramp from 0 to 0.5 mM was applied at a fixed albumin concentration of 0.15 mM so that the molar PA/BSA ratio changed within the physiological range. At a fixed concentration of 0.5 mM, PA markedly inhibited acetylcholine-stimulated insulin release, the rise of intracellular Ca(2+), and enhancement of cAMP production but did not influence the effects of GLP-1 on these parameters of islet cell function. 2-ADB, an IP(3) receptor inhibitor, reduced the effect of acetylcholine on insulin secretion and reversed the effect of PA on acetylcholine-stimulated insulin release. Islet perfusion for 35-40 min with 0.5 mM PA significantly reduced the calcium storage capacity of ER measured by the thapsigargin-induced Ca(2+) release. Oxygen consumption due to low but not high glucose was reduced by PA. When a PA ramp from 0 to 0.5 mM was applied in the presence of 8 mM glucose, PA at concentrations as low as 50 microM significantly augmented glucose-stimulated insulin release and markedly reduced acetylcholine's effects on hormone secretion. We thus demonstrate that PA acutely reduces the total oxygen consumption response to glucose, glucose-dependent acetylcholine stimulation of insulin release, Ca(2+), and cAMP metabolism, whereas GLP-1's actions on these parameters remain unaffected or potentiated. We speculate that acute emptying of the ER calcium by PA results in decreased glucose stimulation of respiration and acetylcholine potentiation of insulin secretion.
Topics: Acetylcholine; Animals; Calcium; Cyclic AMP; Glucagon-Like Peptide 1; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Inbred C57BL; Oxygen Consumption; Palmitic Acid
PubMed: 20606076
DOI: 10.1152/ajpendo.00072.2010 -
Function (Oxford, England) 2022Postjunctional M2Rs on airway smooth muscle (ASM) outnumber M3Rs by a ratio of 4:1 in most species, however, it is the M3Rs that are thought to mediate the...
Postjunctional M2Rs on airway smooth muscle (ASM) outnumber M3Rs by a ratio of 4:1 in most species, however, it is the M3Rs that are thought to mediate the bronchoconstrictor effects of acetylcholine. In this study, we describe a novel and profound M2R-mediated hypersensitization of M3R-dependent contractions of ASM at low stimulus frequencies.. Contractions induced by 2Hz EFS were augmented by > 2.5-fold when the stimulus interval was reduced from 100 to 10 s. This effect was reversed by the M2R antagonists, methoctramine, and AFDX116, and was absent in M2R null mice. The M3R antagonist 4-DAMP abolished the entire response in both WT and M2R KO mice. The M2R-mediated potentiation of EFS-induced contractions was not observed when the stimulus frequency was increased to 20 Hz. A subthreshold concentration of carbachol enhanced the amplitude of EFS-evoked contractions in WT, but not M2R null mice. These data highlight a significant M2R-mediated potentiation of M3R-dependent contractions of ASM at low frequency stimulation that could be relevant in diseases such as asthma and COPD.
Topics: Mice; Animals; Muscle Contraction; Receptors, Muscarinic; Muscle, Smooth; Acetylcholine; Cholinergic Agents
PubMed: 35330928
DOI: 10.1093/function/zqab053 -
Neuroscience Bulletin May 2023Acetylcholine (ACh) is an important neuromodulator in various cognitive functions. However, it is unclear how ACh influences neural circuit dynamics by altering cellular...
Acetylcholine (ACh) is an important neuromodulator in various cognitive functions. However, it is unclear how ACh influences neural circuit dynamics by altering cellular properties. Here, we investigated how ACh influences reverberatory activity in cultured neuronal networks. We found that ACh suppressed the occurrence of evoked reverberation at low to moderate doses, but to a much lesser extent at high doses. Moreover, high doses of ACh caused a longer duration of evoked reverberation, and a higher occurrence of spontaneous activity. With whole-cell recording from single neurons, we found that ACh inhibited excitatory postsynaptic currents (EPSCs) while elevating neuronal firing in a dose-dependent manner. Furthermore, all ACh-induced cellular and network changes were blocked by muscarinic, but not nicotinic receptor antagonists. With computational modeling, we found that simulated changes in EPSCs and the excitability of single cells mimicking the effects of ACh indeed modulated the evoked network reverberation similar to experimental observations. Thus, ACh modulates network dynamics in a biphasic fashion, probably by inhibiting excitatory synaptic transmission and facilitating neuronal excitability through muscarinic signaling pathways.
Topics: Cholinergic Agents; Acetylcholine; Neurons; Synaptic Transmission
PubMed: 36670292
DOI: 10.1007/s12264-022-01012-7 -
British Journal of Pharmacology and... Mar 1952
Topics: Acetylcholine; Esophagus; Movement; Trachea
PubMed: 14904904
DOI: 10.1111/j.1476-5381.1952.tb00691.x -
The Journal of Physiology Aug 19891. The effects of vagal stimulation and applied acetylcholine were compared on the isolated sinus venosus preparation of the toad, Bufo marinus. 2. The effects of...
1. The effects of vagal stimulation and applied acetylcholine were compared on the isolated sinus venosus preparation of the toad, Bufo marinus. 2. The effects of applied acetylcholine and of low-frequency, or short bursts of high-frequency vagal stimulation were abolished by hyoscine. 3. When intracellular recordings were made from muscle cells of the sinus venosus, it was found that applied acetylcholine caused bradycardia and a cessation of the heart beat which was associated with membrane hyperpolarization and a reduction in the duration of the action potentials. Much of the effect of acetylcholine can be attributed to it causing an increase in potassium conductance, gK. 4. When slowing was produced by low-frequency vagal stimulation, only a small increase in maximum diastolic potential was detected. During vagal arrest the membrane potential settled to a potential positive of the control maximum diastolic potential. 5. In the presence of barium, much of the bradycardia associated with vagal stimulation persisted. Although the bradycardia produced by added acetylcholine also persisted in the presence of barium, the effects of acetylcholine that could be attributed to an increase in gK were abolished. 6. Addition of caesium ions produced bradycardia with membrane potential changes similar to those seen during vagal stimulation. 7. The results are discussed in relation to the idea that neuronally released acetylcholine reduces inward current flow during diastole. In contrast applied acetylcholine as well as reducing inward current flow during diastole also increases outward current flow by increasing gK.
Topics: Acetylcholine; Action Potentials; Animals; Barium; Bufo marinus; Cesium; Heart; Heart Rate; Membrane Potentials; Nifedipine; Scopolamine; Tetrodotoxin; Vagus Nerve
PubMed: 2517987
DOI: 10.1113/jphysiol.1989.sp017710 -
The Journal of Investigative Dermatology Aug 1948
Topics: Acetylcholine; Humans; Pilocarpine; Sweat Glands
PubMed: 18877039
DOI: 10.1038/jid.1948.78