Nonsynaptic Chemical Transmission Through Nicotinic Acetylcholine Receptors

2008 ◽  
Vol 88 (2) ◽  
pp. 333-349 ◽  
Author(s):  
Balázs Lendvai ◽  
E. Sylvester Vizi
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Neural Plasticity ◽  
Acetylcholine Receptors ◽  
Human Subjects ◽  
Brain Regions ◽  
Nicotinic Acetylcholine ◽  
Basic Activity ◽  
The Central Nervous System ◽  
Steady State Levels ◽  
Fast Activation

This review attempts to organize the different aspects of nicotinic transmission in the context of nonsynaptic interactions. Nicotinic acetylcholine receptors (nAChRs) dominantly operate in the nonsynaptic mode in the central nervous system despite their ligand-gated ion-channel nature, which would otherwise be better suited for fast synaptic transmission. This fast form of nonsynaptic transmission, most likely unique to nAChRs, represents a new avenue in the communication platforms of the brain. Cholinergic messages received by nAChRs, arriving at a later phase following synaptic activation, can interfere with dendritic signal integration. Nicotinic transmission plays a role in both neural plasticity and cellular learning processes, as well as in long-term changes in basic activity through fast activation, desensitization of receptors, and fluctuations of the steady-state levels of ACh. ACh release can contribute to plastic changes via activation of nAChRs in neurons and therefore plays a role in learning and memory in different brain regions. Assuming that nAChRs in human subjects are ready to receive long-lasting messages from the extracellular space because of their predominantly nonsynaptic distribution, they offer an ideal target for drug therapy at low, nontoxic drug levels.

scholarly journals NMR Structure and Action on Nicotinic Acetylcholine Receptors of Water-soluble Domain of Human LYNX1

2011 ◽  
Vol 286 (12) ◽  
pp. 10618-10627 ◽  
Author(s):  
Ekaterina N. Lyukmanova ◽  
Zakhar O. Shenkarev ◽  
Mikhail A. Shulepko ◽  
Konstantin S. Mineev ◽  
Dieter D'Hoedt ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nmr Structure ◽  
Water Soluble ◽  
Gpi Anchor ◽  
Nicotinic Acetylcholine ◽  
Brain Functions ◽  
The Central Nervous System ◽  
High Concentrations

Discovery of proteins expressed in the central nervous system sharing the three-finger structure with snake α-neurotoxins provoked much interest to their role in brain functions. Prototoxin LYNX1, having homology both to Ly6 proteins and three-finger neurotoxins, is the first identified member of this family membrane-tethered by a GPI anchor, which considerably complicates in vitro studies. We report for the first time the NMR spatial structure for the water-soluble domain of human LYNX1 lacking a GPI anchor (ws-LYNX1) and its concentration-dependent activity on nicotinic acetylcholine receptors (nAChRs). At 5–30 μm, ws-LYNX1 competed with 125I-α-bungarotoxin for binding to the acetylcholine-binding proteins (AChBPs) and to Torpedo nAChR. Exposure of Xenopus oocytes expressing α7 nAChRs to 1 μm ws-LYNX1 enhanced the response to acetylcholine, but no effect was detected on α4β2 and α3β2 nAChRs. Increasing ws-LYNX1 concentration to 10 μm caused a modest inhibition of these three nAChR subtypes. A common feature for ws-LYNX1 and LYNX1 is a decrease of nAChR sensitivity to high concentrations of acetylcholine. NMR and functional analysis both demonstrate that ws-LYNX1 is an appropriate model to shed light on the mechanism of LYNX1 action. Computer modeling, based on ws-LYNX1 NMR structure and AChBP x-ray structure, revealed a possible mode of ws-LYNX1 binding.

scholarly journals Acute Administration of Desformylflustrabromine Relieves Chemically Induced Pain in CD-1 Mice

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 944 ◽  
Author(s):  
Loni Weggel ◽  
Anshul Pandya
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Acute Administration ◽  
Allosteric Modulators ◽  
Neuronal Nicotinic Acetylcholine Receptors ◽  
Nicotinic Acetylcholine ◽  
Chemically Induced ◽  
The Central Nervous System ◽  
Membrane Bound ◽  
Pain Test

Neuronal nicotinic acetylcholine receptors are cell membrane-bound ion channels that are widely distributed in the central nervous system. The α4β2 subtype of neuronal nicotinic acetylcholine receptor plays an important role in modulating the signaling pathways for pain. Previous studies have shown that agonists, partial agonists, and positive allosteric modulators for the α4β2 receptors are effective in relieving pain. Desformylflustrabromine is a compound that acts as an allosteric modulator of α4β2 receptors. The aim of this study was to assess the effects of desformylflustrabromine on chemically induced pain. For this purpose, the formalin-induced pain test and the acetic acid-induced writhing response test were carried out in CD-1 mice. Both tests represent chemical assays for nociception. The results show that desformylflustrabromine is effective in producing an analgesic effect in both tests used for assessing nociception. These results suggest that desformylflustrabromine has the potential to become a clinically used drug for pain relief.

Differential Sensitivities of Mammalian Neuronal and Muscle Nicotinic Acetylcholine Receptors to General Anesthetics 

1997 ◽  
Vol 86 (4) ◽  
pp. 866-874 ◽  
Author(s):  
J. M. Violet ◽  
D. L. Downie ◽  
R. C. Nakisa ◽  
W. R. Lieb ◽  
N. P. Franks
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Xenopus Oocytes ◽  
General Anesthetics ◽  
Response Curves ◽  
Nicotinic Acetylcholine ◽  
Considerable Uncertainty ◽  
Messenger Ribonucleic Acid ◽  
The Central Nervous System ◽  
Type 3

Background Nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of fast neurotransmitter-gated receptor channels that includes the gamma-aminobutyric acidA (GABAA), glycine and serotonin type 3 (5-HT3) receptors. Most previous work on the interactions of general anesthetics with nAChRs has involved the muscle-type receptor. The authors investigate the effects of general anesthetics on defined mammalian neuronal and muscle nAChRs expressed in Xenopus oocytes. Methods Complementary deoxyribonucleic acid (cDNA) or messenger ribonucleic acid (mRNA) encoding for various neuronal or muscle nAChR subunits was injected into Xenopus oocytes, and the resulting ACh-activated currents were studied using the two-electrode voltage-clamp technique. The effects of halothane, isoflurane, sevoflurane, and propofol on the peak acetylcholine-induced currents were investigated, and concentration-response curves were constructed. Results The neuronal nAChRs were found to be much more sensitive to general anesthetics than were the muscle nAChRs, with IC50 concentrations being 10- to 35-fold less for the neuronal receptors. For the inhalational general anesthetics, the IC50 concentrations were considerably less than the free aqueous concentrations that cause general anesthesia in mammals. In addition, qualitative (dependence on acetylcholine concentration) and quantitative (steepness of concentration-response curves) differences in the anesthetic interactions between the neuronal and muscle nAChRs suggest that different mechanisms of inhibition may be involved. Conclusions Although there is considerable uncertainty about the physiologic roles that neuronal nAChRs play in the central nervous system, their extraordinary sensitivity to general anesthetics, particularly the inhalational agents, suggests they may mediate some of the effects of general anesthetics at surgical, or even subanesthetic, concentrations.

Nicotinic Acetylcholine Receptors

2018 ◽  
Author(s):  
Roger L. Papke
Keyword(s):  
Ion Channels ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Neuromuscular Junctions ◽  
Cognitive Disorders ◽  
The Body ◽  
Nicotinic Acetylcholine ◽  
Synaptic Receptors ◽  
The Central Nervous System ◽  
The Brain

Acetylcholine, exquisitely evolved as a neurotransmitter, is made and released by the neurons that take the integrated output of the central nervous system throughout the body. At both neuromuscular junctions and autonomic ganglia, acetylcholine activates synaptic ion channels that take their name from the plant alkaloid nicotine, which is a mimic of the natural neurotransmitter. This chapter begins with the scientific discoveries related to the nicotinic acetylcholine receptors (nAChR) of the neuromuscular junction and how resulting insights led to an understanding of the fundamentals of synaptic transmission. The nAChR are one member of a superfamily of ligand-gated ion channels, and although in the brain excitatory neurotransmission is mediated by another family of synaptic receptors that are gated by glutamate, nicotinic receptors are important modulators of brain function and significant targets for drug development. In the brain, nAChR are targets for cognitive disorders and, tragically, responsible for tobacco addiction.

Alpha4beta2 Neuronal Nicotinic Acetylcholine Receptors in the Central Nervous System Are Inhibited by Isoflurane and Propofol, but alpha7-type Nicotinic Acetylcholine Receptors Are Unaffected 

1997 ◽  
Vol 86 (4) ◽  
pp. 859-865 ◽  
Author(s):  
Pamela Flood ◽  
Jose Ramirez-Latorre ◽  
Lorna Role
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
General Anesthetics ◽  
Nicotinic Acetylcholine ◽  
The Central Nervous System ◽  
Beta 2 ◽  
Alpha 7

Background The mechanisms of action of general anesthetics are not completely understood. Many general anesthetics are reported to potentiate gamma-aminobutyric acid (GABAA) and glycine receptors in the central nervous system (CNS) and to inhibit the muscle-type nicotinic acetylcholine receptor (nAChR). The effects of general anesthetics on another family of ligand-gated ion channel in the CNS, the nAChRs, have not been defined. Methods Two types of CNS acetylcholine receptor, the alpha 4 beta 2 receptor or the alpha 7 homomeric receptor, were expressed heterologously in Xenopus laevis oocytes. Using the standard two-microelectrode voltage-clamp technique, peak acetylcholinegated current was measured before and after coapplication of isoflurane or propofol. Results Coapplication of either isoflurane or propofol with acetylcholine resulted in potent, dose-dependent inhibition of the alpha 4 beta 2 receptor current with median inhibitory concentrations of 85 and 19 microM, respectively. The inhibition of the alpha 4 beta 2 receptor by both isoflurane and propofol appears to be competitive with respect to acetylcholine. The alpha 7 receptor current was not effected by either anesthetic. Conclusions The CNS-type nAChRs are differentially affected by isoflurane and propofol. The alpha 4 beta 2 receptor is affected by isoflurane more potently than the most sensitive GABAA or glycine receptor that has been reported, whereas the alpha 7 homomeric receptor is not affected by either anesthetic. Inhibition of specific subtypes of nAChRs in the CNS, along with potentiation of GABAA and glycine receptors, may contribute to the effects and side effects of general anesthetics.

scholarly journals High-Throughput Patch Clamp Screening in Human α6-Containing Nicotinic Acetylcholine Receptors

2017 ◽  
Vol 22 (6) ◽  
pp. 686-695 ◽  
Author(s):  
Lucas C. Armstrong ◽  
Glenn E. Kirsch ◽  
Nikolai B. Fedorov ◽  
Caiyun Wu ◽  
Yuri A. Kuryshev ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Cell Line ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Brain Regions ◽  
Tobacco Product ◽  
Tobacco Products ◽  
Nicotinic Acetylcholine ◽  
Automated Patch Clamp ◽  
Subtype Selective

Nicotine, the addictive component of tobacco products, is an agonist at nicotinic acetylcholine receptors (nAChRs) in the brain. The subtypes of nAChR are defined by their α- and β-subunit composition. The α6β2β3 nAChR subtype is expressed in terminals of dopaminergic neurons that project to the nucleus accumbens and striatum and modulate dopamine release in brain regions involved in nicotine addiction. Although subtype-dependent selectivity of nicotine is well documented, subtype-selective profiles of other tobacco product constituents are largely unknown and could be essential for understanding the addiction-related neurological effects of tobacco products. We describe the development and validation of a recombinant cell line expressing human α6/3β2β3V273S nAChR for screening and profiling assays in an automated patch clamp platform (IonWorks Barracuda). The cell line was pharmacologically characterized by subtype-selective and nonselective reference agonists, pore blockers, and competitive antagonists. Agonist and antagonist effects detected by the automated patch clamp approach were comparable to those obtained by conventional electrophysiological assays. A pilot screen of a library of Food and Drug Administration–approved drugs identified compounds, previously not known to modulate nAChRs, which selectively inhibited the α6/3β2β3V273S subtype. These assays provide new tools for screening and subtype-selective profiling of compounds that act at α6β2β3 nicotinic receptors.

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