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Neuropharmacology Jul 2020Here we begin by briefly reviewing landmark structural studies on the nicotinic acetylcholine receptor. We highlight challenges that had to be overcome to push through... (Review)
Review
Here we begin by briefly reviewing landmark structural studies on the nicotinic acetylcholine receptor. We highlight challenges that had to be overcome to push through resolution barriers, then focus on what has been gleaned in the past few years from crystallographic and single particle cryo-EM studies of different nicotinic receptor subunit assemblies and ligand complexes. We discuss insights into ligand recognition, ion permeation, and allosteric gating. We then highlight some foundational aspects of nicotinic receptor structural biology that remain unresolved and are areas ripe for future exploration. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
Topics: Animals; Cryoelectron Microscopy; Crystallography; Humans; Receptors, Nicotinic
PubMed: 32272141
DOI: 10.1016/j.neuropharm.2020.108086 -
Neuropharmacology Oct 2020Nicotinic acetylcholine receptors (nAChR) are homo- or hetero-pentameric ligand-gated ion channels of the Cys-loop superfamily and play important roles in the nervous... (Review)
Review
Nicotinic acetylcholine receptors (nAChR) are homo- or hetero-pentameric ligand-gated ion channels of the Cys-loop superfamily and play important roles in the nervous system and muscles. Studies on nAChR benefit from in silico modeling due to the lack of high-resolution structures for most receptor subtypes and challenges in experiments addressing the complex mechanism of activation involving allosteric sites. Although there is myriad of computational modeling studies on nAChR, the multitude of the methods and parameters used in these studies makes modeling nAChR a daunting task, particularly for the non-experts in the field. To address this problem, the modeling literature on Torpedo nAChR and α7 nAChR were focused on as examples of heteromeric and homomeric nAChR, and the key in silico modeling studies between the years 1995-2019 were concisely reviewed. This was followed by a critical analysis of these studies by comparing the findings with each other and with the emerging experimental and computational data on nAChR. Based on these critical analyses, suggestions were made to guide the future researchers in the field of in silico modeling of nAChR. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.
Topics: Allosteric Regulation; Animals; Binding Sites; Computer Simulation; Humans; Models, Molecular; Protein Structure, Secondary; Receptors, Nicotinic
PubMed: 32738311
DOI: 10.1016/j.neuropharm.2020.108257 -
International Journal of Molecular... Sep 2023Nicotine, the primary psychoactive agent in tobacco leaves, has led to the widespread use of tobacco, with over one billion smokers globally. This article provides a... (Review)
Review
Nicotine, the primary psychoactive agent in tobacco leaves, has led to the widespread use of tobacco, with over one billion smokers globally. This article provides a historical overview of tobacco and discusses tobacco dependence, as well as the biological effects induced by nicotine on mammalian cells. Nicotine induces various biological effects, such as neoangiogenesis, cell division, and proliferation, and it affects neural and non-neural cells through specific pathways downstream of nicotinic receptors (nAChRs). Specific effects mediated by α7 nAChRs are highlighted. Nicotine is highly addictive and hazardous. Public health initiatives should prioritize combating smoking and its associated risks. Understanding nicotine's complex biological effects is essential for comprehensive research and informed health policies. While potential links between nicotine and COVID-19 severity warrant further investigation, smoking remains a significant cause of morbidity and mortality globally. Effective public health strategies are vital to promote healthier lifestyles.
Topics: Animals; Humans; Nicotine; Receptors, Nicotinic; Smoking; Tobacco Use Disorder; Mammals
PubMed: 37834017
DOI: 10.3390/ijms241914570 -
Neuron Apr 2022Fast synaptic communication requires receptors that respond to the presence of neurotransmitter by opening an ion channel across the post-synaptic membrane. The...
Fast synaptic communication requires receptors that respond to the presence of neurotransmitter by opening an ion channel across the post-synaptic membrane. The muscle-type nicotinic acetylcholine receptor from the electric fish, Torpedo, is the prototypic ligand-gated ion channel, yet the structural changes underlying channel activation remain undefined. Here we use cryo-EM to solve apo and agonist-bound structures of the Torpedo nicotinic receptor embedded in a lipid nanodisc. Using both a direct biochemical assay to define the conformational landscape and molecular dynamics simulations to assay flux through the pore, we correlate structures with functional states and elucidate the motions that lead to pore activation of a heteromeric nicotinic receptor. We highlight an underappreciated role for the complementary subunit in channel gating, establish the structural basis for the differential agonist affinities of α/δ versus α /γ sites, and explain why nicotine is less potent at muscle nicotinic receptors compared to neuronal ones.
Topics: Animals; Binding Sites; Ligand-Gated Ion Channels; Ligands; Muscles; Receptors, Nicotinic; Torpedo
PubMed: 35139364
DOI: 10.1016/j.neuron.2022.01.013 -
Nature Structural & Molecular Biology Apr 2022Binding of the neurotransmitter acetylcholine to its receptors on muscle fibers depolarizes the membrane and thereby triggers muscle contraction. We sought to understand...
Binding of the neurotransmitter acetylcholine to its receptors on muscle fibers depolarizes the membrane and thereby triggers muscle contraction. We sought to understand at the level of three-dimensional structure how agonists and antagonists alter nicotinic acetylcholine receptor conformation. We used the muscle-type receptor from the Torpedo ray to first define the structure of the receptor in a resting, activatable state. We then determined the receptor structure bound to the agonist carbachol, which stabilizes an asymmetric, closed channel desensitized state. We find conformational changes in a peripheral membrane helix are tied to recovery from desensitization. To probe mechanisms of antagonism, we obtained receptor structures with the active component of curare, a poison arrow toxin and precursor to modern muscle relaxants. d-Tubocurarine stabilizes the receptor in a desensitized-like state in the presence and absence of agonist. These findings define the transitions between resting and desensitized states and reveal divergent means by which antagonists block channel activity of the muscle-type nicotinic receptor.
Topics: Animals; Binding Sites; Curare; Muscles; Receptors, Nicotinic; Torpedo
PubMed: 35301478
DOI: 10.1038/s41594-022-00737-3 -
Molecular Aspects of Medicine Apr 2022We propose an extension and further development of the Monod-Wyman-Changeux model for allosteric transitions of regulatory proteins to brain communications and... (Review)
Review
We propose an extension and further development of the Monod-Wyman-Changeux model for allosteric transitions of regulatory proteins to brain communications and specifically to neurotransmitters receptors, with the nicotinic acetylcholine receptor (nAChR) as a model of ligand-gated ion channels. The present development offers an expression of the change of the gating isomerization constant caused by pharmacological ligand binding in terms of its value in the absence of ligands and several "modulation factors", which vary with orthosteric ligand binding (agonists/antagonists), allosteric ligand binding (positive allosteric modulators/negative allosteric modulators) and receptor desensitization. The new - explicit - formulation of such "modulation factors", provides expressions for the pharmacological attributes of potency, efficacy, and selectivity for the modulatory ligands (including endogenous neurotransmitters) in terms of their binding affinity for the active, resting, and desensitized states of the receptor. The current formulation provides ways to design neuroactive compounds with a controlled pharmacological profile, opening the field of computational neuro-pharmacology.
Topics: Allosteric Regulation; Humans; Ligands; Neuropharmacology; Receptors, Nicotinic
PubMed: 34656371
DOI: 10.1016/j.mam.2021.101044 -
Biochemical Pharmacology Oct 2013Nicotine has been shown in a variety of studies to improve cognitive function including learning, memory and attention. Nicotine both stimulates and desensitizes... (Review)
Review
Nicotine has been shown in a variety of studies to improve cognitive function including learning, memory and attention. Nicotine both stimulates and desensitizes nicotinic receptors, thus acting both as an agonist and a net antagonist. The relative roles of these two actions for nicotine-induced cognitive improvement have not yet been fully determined. We and others have found that acute nicotinic antagonist treatment can improve learning and attention. Nicotine acts on a variety of nicotinic receptor subtypes. The relative role and interactions of neuronal nicotinic receptor subtypes for cognition also needs to be better characterized. Nicotine acts on nicotinic receptors in a wide variety of brain areas. The role of some of these areas such as the hippocampus has been relatively well studied but other areas like the thalamus, which has the densest nicotinic receptor concentration are still only partially characterized. In a series of studies we characterized nicotinic receptor actions, anatomic localization and circuit interactions, which are critical to nicotine effects on the cognitive functions of learning, memory and attention. The relative role of increases and decreases in nicotinic receptor activation by nicotine were determined in regionally specific studies of the hippocampus, the amygdala, the frontal cortex and the mediodorsal thalamic nucleus with local infusions of antagonists of nicotinic receptor subtypes (α7 and α4β2). The understanding of the functional neural bases of cognitive function is fundamental to the more effective development of nicotinic drugs for treating cognitive dysfunction.
Topics: Cholinergic Agents; Cognition; Cognition Disorders; Gene Expression Regulation; Humans; Receptors, Nicotinic
PubMed: 23928190
DOI: 10.1016/j.bcp.2013.07.021 -
Neuroscience Aug 2021Although ionotropic glutamate receptors and nicotinic receptors for acetylcholine (ACh) have usually been studied separately, they are often co-localized and... (Review)
Review
Although ionotropic glutamate receptors and nicotinic receptors for acetylcholine (ACh) have usually been studied separately, they are often co-localized and functionally inter-dependent. The objective of this review is to survey the evidence for interactions between the two receptor families and the mechanisms underlying them. These include the mutual regulation of subunit expression, which change the NMDA:AMPA response balance, and the existence of multi-functional receptor complexes which make it difficult to distinguish between individual receptor sites, especially in vivo. This is followed by analysis of the functional relationships between the receptors from work on transmitter release, cellular electrophysiology and aspects of behavior where these can contribute to understanding receptor interactions. It is clear that nicotinic receptors (nAChRs) on axonal terminals directly regulate the release of glutamate and other neurotransmitters, α7-nAChRs generally promoting release. Hence, α7-nAChR responses will be prevented not only by a nicotinic antagonist, but also by compounds blocking the indirectly activated glutamate receptors. This accounts for the apparent anticholinergic activity of some glutamate antagonists, including the endogenous antagonist kynurenic acid. The activation of presynaptic nAChRs is by the ambient levels of ACh released from pre-terminal synapses, varicosities and glial cells, acting as a 'volume neurotransmitter' on synaptic and extrasynaptic sites. In addition, ACh and glutamate are released as CNS co-transmitters, including 'cholinergic' synapses onto spinal Renshaw cells. It is concluded that ACh should be viewed primarily as a modulator of glutamatergic neurotransmission by regulating the release of glutamate presynaptically, and the location, subunit composition, subtype balance and sensitivity of glutamate receptors, and not primarily as a classical fast neurotransmitter. These conclusions and caveats should aid clarification of the sites of action of glutamate and nicotinic receptor ligands in the search for new centrally-acting drugs.
Topics: Glutamic Acid; Nicotinic Antagonists; Receptors, Ionotropic Glutamate; Receptors, Nicotinic; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 34111447
DOI: 10.1016/j.neuroscience.2021.06.007 -
Biomolecules Apr 2020The concept of pharmacological receptor was proposed at the turn of the 20th century but it took almost 70 years before the first receptor for a neurotransmitter was... (Review)
Review
The concept of pharmacological receptor was proposed at the turn of the 20th century but it took almost 70 years before the first receptor for a neurotransmitter was isolated and identified as a protein. This review retraces the history of the difficulties and successes in the identification of the nicotinic acetylcholine receptor, the first neurotransmitter receptor to be identified.
Topics: Animals; Drug Discovery; Humans; Receptors, Nicotinic
PubMed: 32260196
DOI: 10.3390/biom10040547 -
Pharmacological Research May 2023Initiated by findings that Alzheimer's disease is associated with a profound loss of cholinergic markers in human brain, decades of studies have examined the... (Review)
Review
Initiated by findings that Alzheimer's disease is associated with a profound loss of cholinergic markers in human brain, decades of studies have examined the interactions between specific subtypes of nicotinic acetylcholine receptors and amyloid-β [derived from the amyloid precursor protein (APP), which is cleaved to yield variable isoforms of amyloid-β]. We review the evolving understanding of amyloid-β's roles in Alzheimer's disease and pioneering studies that highlighted a role of nicotinic acetylcholine receptors in mediating important aspects of amyloid-β's effects. This review also surveys the current state of research into amyloid-β / nicotinic acetylcholine receptor interactions. The field has reached an exciting point in which common themes are emerging from the wide range of prior research and a range of accessible, relevant model systems are available to drive further progress. We highlight exciting new areas of inquiry and persistent challenges that need to be considered while conducting this research. Studies of amyloid-β and the nicotinic acetylcholine receptor populations that it interacts with provide opportunities for innovative basic and translational scientific breakthroughs related to nicotinic receptor biology, Alzheimer's disease, and cholinergic contributions to cognition more broadly.
Topics: Animals; Humans; Receptors, Nicotinic; Alzheimer Disease; alpha7 Nicotinic Acetylcholine Receptor; Amyloid beta-Peptides; Cholinergic Agents; Disease Models, Animal
PubMed: 37084859
DOI: 10.1016/j.phrs.2023.106743