scholarly journals Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function

2009 ◽  
Vol 89 (1) ◽  
pp. 73-120 ◽  
Author(s):  
Edson X. Albuquerque ◽  
Edna F. R. Pereira ◽  
Manickavasagom Alkondon ◽  
Scott W. Rogers
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Drugs Of Abuse ◽  
Electric Organ ◽  
The Body ◽  
Mammalian Brain ◽  
Comprehensive Overview ◽  
Rich Diversity ◽  
The Rich ◽  
The Impact

The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of α-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.

The Oxford Handbook of Feminist Philosophy

2021 ◽  
Keyword(s):  
Critical Race Theory ◽  
Queer Theory ◽  
Postcolonial Theory ◽  
The Body ◽  
Feminist Philosophy ◽  
Comprehensive Overview ◽  
Rich Diversity ◽  
Trans Studies ◽  
Feminist Perspectives ◽  
The Rich

This exciting new Handbook offers a comprehensive overview of the contemporary state of the field. The editors’ introduction and forty-five essays cover feminist critical engagements with philosophy and adjacent scholarly fields, as well as feminist approaches to current debates and crises across the world. Authors cover topics ranging from the ways in which feminist philosophy attends to other systems of oppression, and the gendered, racialized, and classed assumptions embedded in philosophical concepts, to feminist perspectives on prominent subfields of philosophy. The first section contains chapters that explore feminist philosophical engagement with mainstream and marginalized histories and traditions, while the second section parses feminist philosophy’s contributions to with numerous philosophical subfields, for example metaphysics and bioethics. A third section explores what feminist philosophy can illuminate about crucial moral and political issues of identity, gender, the body, autonomy, prisons, among numerous others. The Handbook concludes with the field’s engagement with other theories and movements, including trans studies, queer theory, critical race, theory, postcolonial theory, and decolonial theory. The volume provides a rigorous but accessible resource for students and scholars who are interested in feminist philosophy, and how feminist philosophers situate their work in relation to the philosophical mainstream and other disciplines. Above all it aims to showcase the rich diversity of subject matter, approach, and method among feminist philosophers.

scholarly journals Interactions of Nereistoxin and Its Analogs with Vertebrate Nicotinic Acetylcholine Receptors and Molluscan ACh Binding Proteins

Marine Drugs ◽  
2022 ◽  
Vol 20 (1) ◽  
pp. 49
Author(s):  
William Kem ◽  
Kristin Andrud ◽  
Galen Bruno ◽  
Hong Xing ◽  
Ferenc Soti ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Specific Radioactivity ◽  
Electric Organ ◽  
Binding Affinities ◽  
Nicotinic Acetylcholine ◽  
High Affinity ◽  
High Specific Radioactivity ◽  
Alpha Bungarotoxin

Nereistoxin (NTX) is a marine toxin isolated from an annelid worm that lives along the coasts of Japan. Its insecticidal properties were discovered decades ago and this stimulated the development of a variety of insecticides such as Cartap that are readily transformed into NTX. One unusual feature of NTX is that it is a small cyclic molecule that contains a disulfide bond. In spite of its size, it acts as an antagonist at insect and mammalian nicotinic acetylcholine receptors (nAChRs). The functional importance of the disulfide bond was assessed by determining the effects of inserting a methylene group between the two sulfur atoms, creating dimethylaminodithiane (DMA-DT). We also assessed the effect of methylating the NTX and DMA-DT dimethylamino groups on binding to three vertebrate nAChRs. Radioligand receptor binding experiments were carried out using washed membranes from rat brain and fish (Torpedo) electric organ; [3H]-cytisine displacement was used to assess binding to the predominantly high affinity alpha4beta2 nAChRs and [125I]-alpha-bungarotoxin displacement was used to measure binding of NTX and analogs to the alpha7 and skeletal muscle type nAChRs. While the two quaternary nitrogen analogs, relative to their respective tertiary amines, displayed lower α4β2 nAChR binding affinities, both displayed much higher affinities for the Torpedo muscle nAChR and rat alpha7 brain receptors than their respective tertiary amine forms. The binding affinities of DMA-DT for the three nAChRs were lower than those of NTX and MeNTX. An AChBP mutant lacking the C loop disulfide bond that would potentially react with the NTX disulfide bond displayed an NTX affinity very similar to the parent AChBP. Inhibition of [3H]-epibatidine binding to the AChBPs was not affected by exposure to NTX or MeNTX for up to 24 hr prior to addition of the radioligand. Thus, the disulfide bond of NTX is not required to react with the vicinal disulfide in the AChBP C loop for inhibition of [3H]-epibatidine binding. However, a reversible disulfide interchange reaction of NTX with nAChRs might still occur, especially under reducing conditions. Labeled MeNTX, because it can be readily prepared with high specific radioactivity and possesses relatively high affinity for the nAChR-rich Torpedo nAChR, would be a useful probe to detect and identify any nereistoxin adducts.

scholarly journals Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins

2020 ◽  
Vol 14 ◽  
Author(s):  
Thao N. T. Ho ◽  
Nikita Abraham ◽  
Richard J. Lewis
Keyword(s):  
Drug Design ◽  
Ligand Binding ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Rational Drug Design ◽  
Comprehensive Overview ◽  
Nicotinic Acetylcholine ◽  
Structure Based Drug Design ◽  
Selective Ligand

Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.

Interactions of charatoxins and nereistoxin with the nicotinic acetylcholine receptors of insect cns andTorpedo electric organ

1986 ◽  
Vol 3 (5) ◽  
pp. 431-445 ◽  
Author(s):  
Shebl M. Sherby ◽  
Amira T. Eldefrawi ◽  
Jonathan A. David ◽  
David B. Sattelle ◽  
Mohyee E. Eldefrawi
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Electric Organ ◽  
Nicotinic Acetylcholine ◽  
Insect Cns

scholarly journals Neuronal Nicotinic Receptors in Sleep-Related Epilepsy: Studies in Integrative Biology

2012 ◽  
Vol 2012 ◽  
pp. 1-25 ◽  
Author(s):  
Andrea Becchetti
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Single Gene ◽  
Full Range ◽  
Mammalian Brain ◽  
Single Channels ◽  
Heterozygous Condition ◽  
Therapeutic Implications ◽  
Social Burden

Although Mendelian diseases are rare, when considered one by one, overall they constitute a significant social burden. Besides the medical aspects, they propose us one of the most general biological problems. Given the simplest physiological perturbation of an organism, that is, a single gene mutation, how do its effects percolate through the hierarchical biological levels to determine the pathogenesis? And how robust is the physiological system to this perturbation? To solve these problems, the study of genetic epilepsies caused by mutant ion channels presents special advantages, as it can exploit the full range of modern experimental methods. These allow to extend the functional analysis from single channels to whole brains. An instructive example is autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), which can be caused by mutations in neuronal nicotinic acetylcholine receptors. In vitro, such mutations often produce hyperfunctional receptors, at least in heterozygous condition. However, understanding how this leads to sleep-related frontal epilepsy is all but straightforward. Several available animal models are helping us to determine the effects of ADNFLE mutations on the mammalian brain. Because of the complexity of the cholinergic regulation in both developing and mature brains, several pathogenic mechanisms are possible, which also present different therapeutic implications.

scholarly journals Morphological diversity and connectivity of hippocampal interneurons

2018 ◽  
Vol 373 (3) ◽  
pp. 619-641 ◽  
Author(s):  
Sam A. Booker ◽  
Imre Vida
Keyword(s):  
Morphological Diversity ◽  
Inhibitory Neurons ◽  
Mammalian Brain ◽  
Neuronal Function ◽  
Principal Cells ◽  
Axon Terminals ◽  
Efferent Connections ◽  
Rich Diversity ◽  
A Cell ◽  
The Rich

Abstract The mammalian forebrain is constructed from ensembles of neurons that form local microcircuits giving rise to the exquisite cognitive tasks the mammalian brain can perform. Hippocampal neuronal circuits comprise populations of relatively homogenous excitatory neurons, principal cells and exceedingly heterogeneous inhibitory neurons, the interneurons. Interneurons release GABA from their axon terminals and are capable of controlling excitability in every cellular compartment of principal cells and interneurons alike; thus, they provide a brake on excess activity, control the timing of neuronal discharge and provide modulation of synaptic transmission. The dendritic and axonal morphology of interneurons, as well as their afferent and efferent connections within hippocampal circuits, is central to their ability to differentially control excitability, in a cell-type- and compartment-specific manner. This review aims to provide an up-to-date compendium of described hippocampal interneuron subtypes, with respect to their morphology, connectivity, neurochemistry and physiology, a full understanding of which will in time help to explain the rich diversity of neuronal function.

scholarly journals Evaluation of the Phosphoproteome of Mouse Alpha 4/Beta 2-Containing Nicotinic Acetylcholine Receptors In Vitro and In Vivo

Proteomes ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 42 ◽  
Author(s):  
Megan Miller ◽  
Rashaun Wilson ◽  
TuKiet Lam ◽  
Angus Nairn ◽  
Marina Picciotto
Keyword(s):  
Protein Kinase ◽  
Mouse Brain ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Mammalian Brain ◽  
Phosphorylation Sites ◽  
Nicotinic Acetylcholine ◽  
Hek Cells

Activation of nicotinic acetylcholine receptors containing α4 and β2 subunits (α4/β2* nAChRs) in the mammalian brain is necessary for nicotine reinforcement and addiction. We previously identified interactions between α4/β2* nAChRs and calcium/calmodulin-dependent protein kinase II (CaMKII) in mouse and human brain tissue. Following co-expression of α4/β2 nAChR subunits with CaMKII in HEK cells, mass spectrometry identified 8 phosphorylation sites in the α4 subunit. One of these sites and an additional site were identified when isolated α4/β2* nAChRs were dephosphorylated and subsequently incubated with CaMKII in vitro, while 3 phosphorylation sites were identified following incubation with protein kinase A (PKA) in vitro. We then isolated native α4/β2* nAChRs from mouse brain following acute or chronic exposure to nicotine. Two CaMKII sites identified in HEK cells were phosphorylated, and 1 PKA site was dephosphorylated following acute nicotine administration in vivo, whereas phosphorylation of the PKA site was increased back to baseline levels following repeated nicotine exposure. Significant changes in β2 nAChR subunit phosphorylation were not observed under these conditions, but 2 novel sites were identified on this subunit, 1 in HEK cells and 1 in vitro. These experiments identified putative CaMKII and PKA sites on α4/β2* nAChRs and novel nicotine-induced phosphorylation sites in mouse brain that can be explored for their consequences on receptor function.

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.

Rays of the World

2016 ◽  
Keyword(s):  
Comprehensive Overview ◽  
Life Project ◽  
Rich Diversity ◽  
Research Initiative ◽  
Wide Range ◽  
The World ◽  
Distributional Information ◽  
Living Species ◽  
The Rich ◽  
Book Collectors

Rays are among the largest fishes and evolved from shark-like ancestors nearly 200 million years ago. They share with sharks many life history traits: all species are carnivores or scavengers; all reproduce by internal fertilisation; and all have similar morphological and anatomical characteristics, such as skeletons built of cartilage. Rays of the World is the first complete pictorial atlas of the world’s ray fauna and includes information on many species only recently discovered by scientists while undertaking research for the book. It includes all 26 families and 633 valid named species of rays, but additional undescribed species exist for many groups. Rays of the World features a unique collection of paintings of all living species by Australian natural history artist Lindsay Marshall, compiled as part of a multinational research initiative, the Chondrichthyan Tree of Life Project. Images sourced from around the planet were used by the artist to illustrate the fauna. This comprehensive overview of the world’s ray fauna summarises information such as general identifying features and distributional information about these iconic, but surprisingly poorly known, fishes. It will enable readers to gain a better understanding of the rich diversity of rays and promote wider public interest in the group. Rays of the World is an ideal reference for a wide range of readers, including conservationists, fishery managers, scientists, fishers, divers, students and book collectors.

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