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European Biophysics Journal : EBJ Feb 2024The α7 nicotinic acetylcholine receptor is a member of the nicotinic acetylcholine receptor family and is composed of five α7 subunits arranged symmetrically around a...
The α7 nicotinic acetylcholine receptor is a member of the nicotinic acetylcholine receptor family and is composed of five α7 subunits arranged symmetrically around a central pore. It is localized in the central nervous system and immune cells and could be a target for treating Alzheimer's disease and schizophrenia. Acetylcholine is a ligand that opens the channel, although prolonged application rapidly decreases the response. Ivermectin was reported as one of the positive allosteric modulators, since the binding of Ivermectin to the channel enhances acetylcholine-evoked α7 currents. One research has suggested that tilting motions of the nicotinic acetylcholine receptor are responsible for channel opening and activation. To verify this hypothesis applies to α7 nicotinic acetylcholine receptor, we utilized a diffracted X-ray tracking method to monitor the stable twisting and tilting motion of nAChR α7 without a ligand, with acetylcholine, with Ivermectin, and with both of them. The results show that the α7 nicotinic acetylcholine receptor twists counterclockwise with the channel transiently opening, transitioning to a desensitized state in the presence of acetylcholine and clockwise without the channel opening in the presence of Ivermectin. We propose that the conformational transition of ACh-bound nAChR α7 may be due to the collective twisting of the five α7 subunits, resulting in the compression and movement, either downward or upward, of one or more subunits, thus manifesting tilting motions. These tilting motions possibly represent the transition from the resting state to channel opening and potentially to the desensitized state.
Topics: alpha7 Nicotinic Acetylcholine Receptor; Acetylcholine; Ligands; Ivermectin; Receptors, Nicotinic; Allosteric Regulation
PubMed: 38233601
DOI: 10.1007/s00249-023-01693-6 -
Journal of Neurophysiology Sep 2014Sensory information is processed and transmitted through the synaptic structure of local cortical circuits, but it is unclear how modulation of this architecture...
Sensory information is processed and transmitted through the synaptic structure of local cortical circuits, but it is unclear how modulation of this architecture influences the cortical representation of sensory stimuli. Acetylcholine (ACh) promotes attention and arousal and is thought to increase the signal-to-noise ratio of sensory input in primary sensory cortices. Using high-speed two-photon calcium imaging in a thalamocortical somatosensory slice preparation, we recorded action potential activity of up to 900 neurons simultaneously and compared local cortical circuit activations with and without bath presence of ACh. We found that ACh reduced weak pairwise relationships and excluded neurons that were already unreliable during circuit activity. Using action potential activity from the imaged population, we generated functional wiring diagrams based on the statistical dependencies of activity between neurons. ACh pruned weak functional connections from spontaneous circuit activations and yielded a more modular and hierarchical circuit structure, which biased activity to flow in a more feedforward fashion. Neurons that were active in response to thalamic input had reduced pairwise dependencies overall, but strong correlations were conserved. This coincided with a prolonged period during which neurons showed temporally precise responses to thalamic input. Our results demonstrate that ACh reorganizes functional circuit structure in a manner that may enhance the integration and discriminability of thalamic afferent input within local neocortical circuitry.
Topics: Acetylcholine; Animals; Female; Male; Mice; Mice, Inbred C57BL; Neural Pathways; Neurons; Somatosensory Cortex; Thalamus
PubMed: 24872527
DOI: 10.1152/jn.00071.2014 -
Acta Crystallographica. Section D,... Mar 2022Low-nanomolar binding constants were recorded for a series of six 2'-fluoro-(carbamoylpyridinyl)deschloroepibatidine analogues with acetylcholine-binding protein...
Interactions between 2'-fluoro-(carbamoylpyridinyl)deschloroepibatidine analogues and acetylcholine-binding protein inform on potent antagonist activity against nicotinic receptors.
Low-nanomolar binding constants were recorded for a series of six 2'-fluoro-(carbamoylpyridinyl)deschloroepibatidine analogues with acetylcholine-binding protein (AChBP). The crystal structures of three complexes with AChBP reveal details of molecular recognition in the orthosteric binding site and imply how the other three ligands bind. Comparisons exploiting AChBP as a surrogate for α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) suggest that the key interactions are conserved. The ligands interact with the same residues as the archetypal nAChR agonist nicotine yet display greater affinity, thereby rationalizing their in vivo activity as potent antagonists of nicotine-induced antinociception. An oxyanion-binding site is formed on the periphery of the AChBP orthosteric site by Lys42, Asp94, Glu170 and Glu210. These residues are highly conserved in the human α4, β2 and α7 nAChR sequences. However, specific sequence differences are discussed that could contribute to nAChR subtype selectivity and in addition may represent a point of allosteric modulation. The ability to engage with this peripheral site may explain, in part, the function of a subset of ligands to act as agonists of α7 nAChR.
Topics: Acetylcholine; Bridged Bicyclo Compounds, Heterocyclic; Carrier Proteins; Humans; Pyridines; Receptors, Nicotinic
PubMed: 35234149
DOI: 10.1107/S2059798322000754 -
British Journal of Pharmacology Oct 19681. The effects of bretylium on the excitation of postganglionic adrenergic C fibres by acetylcholine and the release of noradrenaline by acetylcholine and electrical...
1. The effects of bretylium on the excitation of postganglionic adrenergic C fibres by acetylcholine and the release of noradrenaline by acetylcholine and electrical stimulation of the splenic nerves have been studied using the in situ and cross perfused cat spleen.2. Close arterial injections of acetylcholine (10-200 mug) evoked a brisk asynchronous discharge in fine filaments of the splenic nerve which reduced the height of the orthodromic C fibre compound action potential.3. Hexamethonium abolished both the excitation of C fibres and release of noradrenaline by acetylcholine, whereas the liberation of noradrenaline by electrical stimulation of the splenic nerves remained unchanged.4. Bretylium (0.5 and 1.0 mg) given close arterially blocked the output of noradrenaline and contractions of the spleen that occurred in response to nerve stimulation (30 c/s) but had much less effect on the responses to acetylcholine.5. Bretylium (2-4 mg) given close arterially blocked the output of noradrenaline and contractions of the spleen caused by both nerve stimulation (30 c/s) and acetylcholine.6. The close arterial injection of (+)-amphetamine sulphate (100 mug) after bretylium (2-4 mg) partially restored the output of noradrenaline and contractions of the spleen to both nerve stimulation and acetylcholine.7. The difference in the sensitivity to blockade by bretylium of the effects of nerve stimulation and the sympathomimetic effects of acetylcholine did not exist if the more "physiological" frequency of stimulation of 10 c/s was employed.8. The close arterial injection of acetylcholine (100 mug) caused a mean average fibre discharge frequency of 5.4 spikes/sec.9. Bretylium in amounts sufficient to completely block the sympathomimetic effects of acetylcholine did not alter the excitation of C fibres by acetylcholine.10. The significance of these results is discussed both in relation to the mode of action of bretylium and to the use of these differential effects of bretylium as evidence for the "cholinergic link" hypothesis.
Topics: Acetylcholine; Action Potentials; Animals; Bretylium Compounds; Cats; Dextroamphetamine; Electric Stimulation; Hexamethonium Compounds; Injections, Intra-Arterial; Norepinephrine; Spleen; Sympathetic Nervous System
PubMed: 5687592
DOI: 10.1111/j.1476-5381.1968.tb07059.x -
Nature Communications Feb 2020Denervation of skeletal muscles induces severe muscle atrophy, which is preceded by cellular alterations such as increased plasma membrane permeability, reduced resting...
Denervation of skeletal muscles induces severe muscle atrophy, which is preceded by cellular alterations such as increased plasma membrane permeability, reduced resting membrane potential and accelerated protein catabolism. The factors that induce these changes remain unknown. Conversely, functional recovery following denervation depends on successful reinnervation. Here, we show that activation of nicotinic acetylcholine receptors (nAChRs) by quantal release of acetylcholine (ACh) from motoneurons is sufficient to prevent changes induced by denervation. Using in vitro assays, ACh and non-hydrolysable ACh analogs repressed the expression of connexin43 and connexin45 hemichannels, which promote muscle atrophy. In co-culture studies, connexin43/45 hemichannel knockout or knockdown increased innervation of muscle fibers by dorsal root ganglion neurons. Our results show that ACh released by motoneurons exerts a hitherto unknown function independent of myofiber contraction. nAChRs and connexin hemichannels are potential molecular targets for therapeutic intervention in a variety of pathological conditions with reduced synaptic neuromuscular transmission.
Topics: Acetylcholine; Animals; Cell Membrane Permeability; Cells, Cultured; Connexin 43; Connexins; Ganglia, Spinal; Male; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Skeletal; Muscular Atrophy; Receptors, Nicotinic
PubMed: 32103010
DOI: 10.1038/s41467-019-14063-8 -
Revue Medicale de Liege Feb 2002A fraction of the vascular endothelial cells may synthetised and release acetylcholine. This release is enhanced by mechanical stimuli such as shear stress or increased... (Review)
Review
A fraction of the vascular endothelial cells may synthetised and release acetylcholine. This release is enhanced by mechanical stimuli such as shear stress or increased blood flow. The physiological role of this release of acetylcholine is explained taking the vasodilatory response to mental stress of blood vessels in skeletal muscles as an example.
Topics: Acetylcholine; Endothelium; Humans; Muscle, Skeletal; Stress, Psychological; Vasoconstriction
PubMed: 11942174
DOI: No ID Found -
Molecular Brain Nov 2022Dopamine-deficient (DD) mice exhibit psychomotor hyperactivity that might be related to a decrease in muscarinic signaling. In the present study, muscarinic...
Dopamine-deficient (DD) mice exhibit psychomotor hyperactivity that might be related to a decrease in muscarinic signaling. In the present study, muscarinic acetylcholine receptor M2 (CHRM2) density decreased in the cortex in DD mice. This is significant because cortical CHRM2 acts as an autoreceptor; therefore, changes in CHRM2 levels could alter acetylcholine in DD mice. We also found that the CHRM1/CHRM4 agonist xanomeline and CHRM2 agonist arecaidine propargyl ester tosylate inhibited hyperactivity in DD mice, suggesting that postsynaptic CHRM1 and CHRM2 and presynaptic CHRM2 may be involved in hyperactivity in DD mice.
Topics: Mice; Animals; Dopamine; Psychomotor Agitation; Acetylcholine; Esters; Signal Transduction
PubMed: 36447257
DOI: 10.1186/s13041-022-00984-x -
PLoS Computational Biology Jun 2022General anesthetics work through a variety of molecular mechanisms while resulting in the common end point of sedation and loss of consciousness. Generally, the...
General anesthetics work through a variety of molecular mechanisms while resulting in the common end point of sedation and loss of consciousness. Generally, the administration of common anesthetics induces reduction in synaptic excitation while promoting synaptic inhibition. Exogenous modulation of the anesthetics' synaptic effects can help determine the neuronal pathways involved in anesthesia. For example, both animal and human studies have shown that exogenously induced increases in acetylcholine in the brain can elicit wakeful-like behavior despite the continued presence of the anesthetic. However, the underlying mechanisms of anesthesia reversal at the cellular level have not been investigated. Here we apply a computational model of a network of excitatory and inhibitory neurons to simulate the network-wide effects of anesthesia, due to changes in synaptic inhibition and excitation, and their reversal by cholinergic activation through muscarinic receptors. We use a differential evolution algorithm to fit model parameters to match measures of spiking activity, neuronal connectivity, and network dynamics recorded in the visual cortex of rodents during anesthesia with desflurane in vivo. We find that facilitating muscarinic receptor effects of acetylcholine on top of anesthetic-induced synaptic changes predicts the reversal of anesthetic suppression of neurons' spiking activity, functional connectivity, as well as pairwise and population interactions. Thus, our model predicts a specific neuronal mechanism for the cholinergic reversal of anesthesia consistent with experimental behavioral observations.
Topics: Acetylcholine; Anesthesia; Anesthetics, General; Animals; Cerebral Cortex; Cholinergic Agents
PubMed: 35737717
DOI: 10.1371/journal.pcbi.1009743 -
ELife Jul 2022In the striatum, acetylcholine (ACh) neuron activity is modulated co-incident with dopamine (DA) release in response to unpredicted rewards and reward-predicting cues...
In the striatum, acetylcholine (ACh) neuron activity is modulated co-incident with dopamine (DA) release in response to unpredicted rewards and reward-predicting cues and both neuromodulators are thought to regulate each other. While this co-regulation has been studied using stimulation studies, the existence of this mutual regulation in vivo during natural behavior is still largely unexplored. One long-standing controversy has been whether striatal DA is responsible for the induction of the cholinergic pause or whether DA D2 receptors (D2Rs) modulate a pause that is induced by other mechanisms. Here, we used genetically encoded sensors in combination with pharmacological and genetic inactivation of D2Rs from cholinergic interneurons (CINs) to simultaneously measure ACh and DA levels after CIN D2R inactivation in mice. We found that CIN D2Rs are not necessary for the initiation of cue-induced decrease in ACh levels. Rather, they prolong the duration of the decrease and inhibit ACh rebound levels. Notably, the change in cue-evoked ACh levels is not associated with altered cue-evoked DA release. Moreover, D2R inactivation strongly decreased the temporal correlation between DA and ACh signals not only at cue presentation but also during the intertrial interval pointing to a general mechanism by which D2Rs coordinate both signals. At the behavioral level D2R antagonism increased the latency to lever press, which was not observed in CIN-selective D2R knock out mice. Press latency correlated with the cue-evoked decrease in ACh levels and artificial inhibition of CINs revealed that longer inhibition shortens the latency to press compared to shorter inhibition. This supports a role of the ACh signal and it's regulation by D2Rs in the motivation to initiate actions.
Topics: Acetylcholine; Animals; Cholinergic Agents; Corpus Striatum; Cues; Dopamine; Mice; Receptors, Dopamine D2
PubMed: 35856493
DOI: 10.7554/eLife.76111 -
The FEBS Journal Nov 2005The discovery of novel biologically active peptides has led to an explosion in our understanding of the molecular mechanisms that underlie the regulation of sleep and... (Review)
Review
The discovery of novel biologically active peptides has led to an explosion in our understanding of the molecular mechanisms that underlie the regulation of sleep and wakefulness. Urotensin II (UII), a peptide originally isolated from fish and known for its strong cardiovascular effects in mammals, is another surprising candidate in the regulatory network of sleep. The UII receptor was found to be expressed by cholinergic neurons of laterodorsal and pedunculopontine tegmental nuclei, an area known to be of utmost importance for the on- and offset of rapid eye movement (REM) sleep. Recently, physiological data have provided further evidence that UII is indeed a modulator of REM sleep. The peptide directly excites cholinergic mesopontine neurons and increases the rate of REM sleep episodes. These new results and its emerging behavioral effects establish UII as a neurotransmitter/neuromodulator in mammals and should spark further interest into the neurobiological role of the peptide.
Topics: Acetylcholine; Animals; Arousal; Heart; Models, Neurological; Neuropeptides; Neurophysiology; Pons; Protein Isoforms; Receptors, G-Protein-Coupled; Receptors, Presynaptic; Sleep, REM; Tegmentum Mesencephali; Urotensins
PubMed: 16279935
DOI: 10.1111/j.1742-4658.2005.04983.x