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Biomolecules
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Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data
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Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-derived Molecules".

Deadline for manuscript submissions: closed (20 April 2020) | Viewed by 40832

Special Issue Editor

Prof. Dr. Victor Tsetlin

E-Mail Website
Guest Editor
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
Interests: peptide and protein neurotoxins, nicotinic and other Cys-loop receptors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This issue will explore the state-of-the-art on acetylcholine and acetylcholine receptors, as important constituents of the cholinergic system. It will include a short history from the discoveries of acetylcholine and nicotinic /muscarinic acetylcholine receptors (nAChRs/ mAChRs) to their cloning and the current knowledge of their spatial structures.

The physiological processes in which acetylcholine and its receptors are involved will be discussed, including signaling cascades following from the metabotropic mAChRs and ligand-gated nAChRs, including those of non-standard metabotropic nAChRs.

Current information on the structure and function of muscle, neuronal, and non-neuronal nAChRs will be presented, including their functions in the nervous and immune systems, as well as information on the diseases (muscle dystrophies, neurodegenerative diseases, channelopathies) associated with their malfunctioning. A special chapter will cover tools, such as peptide and protein neurotoxins, for nAChR analysis.

The advantage of mAChRs is their high-resolution X-ray structures, including those in complexes with agonists/ antagonists and with the G proteins, providing information for understanding the mechanisms of action and opening new lines for drug design. For the latter, new data on the intermediate states of both nAChRs and mAChRs and detailed knowledge of the topography of their orthosteric and allosteric sites are important.

Prof. Victor Tsetlin
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

  • Acetylcholine
  • Nicotinic Acetylcholine Receptor
  • Muscarinic Acetylcholine Receptor
  • X-Ray Analysis
  • Cryo-Electron Microscopy
  • Ligand-Gated Ion Channels
  • Neuronal and Immune Systems
  • Diseases
  • Neurodegenerative Diseases
  • Channelopathies
  • Agonists
  • Antagonists
  • Neurotoxins

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Published Papers (8 papers)

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Editorial

Jump to: Research, Review

3 pages, 167 KiB  
Editorial
Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data
by Victor I. Tsetlin
Biomolecules 2020, 10(6), 852; https://doi.org/10.3390/biom10060852 - 3 Jun 2020
Cited by 12 | Viewed by 4077
Abstract
It was a pleasure to receive a proposal to organize and be a guest editor of a Special Issue of Biomolecules [...] Full article
(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data)

Research

Jump to: Editorial, Review

18 pages, 2976 KiB  
Article
Activation of α7 Nicotinic Acetylcholine Receptor Upregulates HLA-DR and Macrophage Receptors: Potential Role in Adaptive Immunity and in Preventing Immunosuppression
by Andrei E. Siniavin, Maria A. Streltsova, Denis S. Kudryavtsev, Irina V. Shelukhina, Yuri N. Utkin and Victor I. Tsetlin
Biomolecules 2020, 10(4), 507; https://doi.org/10.3390/biom10040507 - 27 Mar 2020
Cited by 29 | Viewed by 5576
Abstract
Immune response during sepsis is characterized by hyper-inflammation followed by immunosuppression. The crucial role of macrophages is well-known for both septic stages, since they are involved in immune homeostasis and inflammation, their dysfunction being implicated in immunosuppression. The cholinergic anti-inflammatory pathway mediated by [...] Read more.
Immune response during sepsis is characterized by hyper-inflammation followed by immunosuppression. The crucial role of macrophages is well-known for both septic stages, since they are involved in immune homeostasis and inflammation, their dysfunction being implicated in immunosuppression. The cholinergic anti-inflammatory pathway mediated by macrophage α7 nicotinic acetylcholine receptor (nAChR) represents possible drug target. Although α7 nAChR activation on macrophages reduces the production of proinflammatory cytokines, the role of these receptors in immunological changes at the cellular level is not fully understood. Using α7 nAChR selective agonist PNU 282,987, we investigated the influence of α7 nAChR activation on the expression of cytokines and, for the first time, of the macrophage membrane markers: cluster of differentiation 14 (CD14), human leukocyte antigen-DR (HLA-DR), CD11b, and CD54. Application of PNU 282,987 to THP-1Mϕ (THP-1 derived macrophages) cells led to inward ion currents and Ca2+ increase in cytoplasm showing the presence of functionally active α7 nAChR. Production of cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 was estimated in classically activated macrophages (M1) and treatment with PNU 282,987 diminished IL-10 expression. α7 nAChR activation on THP-1Mϕ, THP-1M1, and monocyte-derived macrophages (MDMs) increased the expression of HLA-DR, CD54, and CD11b molecules, but decreased CD14 receptor expression, these effects being blocked by alpha (α)-bungarotoxin. Thus, PNU 282,987 enhances the macrophage-mediated immunity via α7 nAChR by regulating expression of their membrane receptors and of cytokines, both playing an important role in preventing immunosuppressive states. Full article
(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data)
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16 pages, 3545 KiB  
Article
Why Does Knocking Out NACHO, But Not RIC3, Completely Block Expression of α7 Nicotinic Receptors in Mouse Brain?
by Anish Deshpande, Remitha M. Vinayakamoorthy, Brijesh K. Garg, Jaya Prakash Thummapudi, Gauri Oza, Ketaki Adhikari, Aayush Agarwal, Parnika Dalvi, Swetha Iyer, Sarulatha Thulasi Raman, Vijay Ramesh, Akshitha Rameshbabu, Alexandra Rezvaya, Sneha Sukumaran, Sweta Swaminathan, Bhargav Tilak, Zhiyuan Wang, Phu V. Tran and Ralph H. Loring
Biomolecules 2020, 10(3), 470; https://doi.org/10.3390/biom10030470 - 19 Mar 2020
Cited by 12 | Viewed by 6382
Abstract
Alpha7 nicotinic acetylcholine receptors (α7nAChRs) are interesting not only because of their physiological effects, but because this receptor requires chaperones to traffic to cell surfaces (measured by alpha-bungarotoxin [αBGT] binding). While knockout (KO) animals and antibodies that react across species exist for tmem35a [...] Read more.
Alpha7 nicotinic acetylcholine receptors (α7nAChRs) are interesting not only because of their physiological effects, but because this receptor requires chaperones to traffic to cell surfaces (measured by alpha-bungarotoxin [αBGT] binding). While knockout (KO) animals and antibodies that react across species exist for tmem35a encoding the protein chaperone NACHO, commercially available antibodies against the chaperone RIC3 that allow Western blots across species have not been generally available. Further, no effects of deleting RIC3 function (ric3 KO) on α7nAChR expression are reported. Finally, antibodies against α7nAChRs have shown various deficiencies. We find mouse macrophages bind αBGT but lack NACHO. We also report on a new α7nAChR antibody and testing commercially available anti-RIC3 antibodies that react across species allowing Western blot analysis of in vitro cultures. These antibodies also react to specific RIC3 splice variants and single-nucleotide polymorphisms. Preliminary autoradiographic analysis reveals that ric3 KOs show subtle αBGT binding changes across different mouse brain regions, while tmem35a KOs show a complete loss of αBGT binding. These findings are inconsistent with effects observed in vitro, as RIC3 promotes αBGT binding to α7nAChRs expressed in HEK cells, even in the absence of NACHO. Collectively, additional regulatory factors are likely involved in the in vivo expression of α7nAChRs. Full article
(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data)
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Graphical abstract

18 pages, 3119 KiB  
Article
Arachidonoylcholine and Other Unsaturated Long-Chain Acylcholines Are Endogenous Modulators of the Acetylcholine Signaling System
by Mikhail G. Akimov, Denis S. Kudryavtsev, Elena V. Kryukova, Elena V. Fomina-Ageeva, Stanislav S. Zakharov, Natalia M. Gretskaya, Galina N. Zinchenko, Igor V. Serkov, Galina F. Makhaeva, Natalia P. Boltneva, Nadezhda V. Kovaleva, Olga G. Serebryakova, Sofya V. Lushchekina, Victor A. Palikov, Yulia Palikova, Igor A. Dyachenko, Igor E. Kasheverov, Victor I. Tsetlin and Vladimir V. Bezuglov
Biomolecules 2020, 10(2), 283; https://doi.org/10.3390/biom10020283 - 12 Feb 2020
Cited by 22 | Viewed by 3924
Abstract
Cholines acylated with unsaturated fatty acids are a recently discovered family of endogenous lipids. However, the data on the biological activity of acylcholines remain very limited. We hypothesized that acylcholines containing residues of arachidonic (AA-CHOL), oleic (Ol-CHOL), linoleic (Ln-CHOL), and docosahexaenoic (DHA-CHOL) acids [...] Read more.
Cholines acylated with unsaturated fatty acids are a recently discovered family of endogenous lipids. However, the data on the biological activity of acylcholines remain very limited. We hypothesized that acylcholines containing residues of arachidonic (AA-CHOL), oleic (Ol-CHOL), linoleic (Ln-CHOL), and docosahexaenoic (DHA-CHOL) acids act as modulators of the acetylcholine signaling system. In the radioligand binding assay, acylcholines showed inhibition in the micromolar range of both α7 neuronal nAChR overexpressed in GH4C1 cells and muscle type nAChR from Torpedo californica, as well as Lymnaea stagnalis acetylcholine binding protein. Functional response was checked in two cell lines endogenously expressing α7 nAChR. In SH-SY5Y cells, these compounds did not induce Ca2+ rise, but inhibited the acetylcholine-evoked Ca2+ rise with IC50 9 to 12 μM. In the A549 lung cancer cells, where α7 nAChR activation stimulates proliferation, Ol-CHOL, Ln-CHOL, and AA-CHOL dose-dependently decreased cell viability by up to 45%. AA-CHOL inhibited human erythrocyte acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) by a mixed type mechanism with Ki = 16.7 ± 1.5 μM and αKi = 51.4 ± 4.1 μM for AChE and Ki = 70.5 ± 6.3 μM and αKi = 214 ± 17 μM for BChE, being a weak substrate of the last enzyme only, agrees with molecular docking results. Thus, long-chain unsaturated acylcholines could be viewed as endogenous modulators of the acetylcholine signaling system. Full article
(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data)
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12 pages, 1914 KiB  
Article
Different Effects of Nicotine and N-Stearoyl-ethanolamine on Episodic Memory and Brain Mitochondria of α7 Nicotinic Acetylcholine Receptor Knockout Mice
by Olena Lykhmus, Olena Kalashnyk, Kateryna Uspenska, Tetyana Horid’ko, Halyna Kosyakova, Serhiy Komisarenko and Maryna Skok
Biomolecules 2020, 10(2), 226; https://doi.org/10.3390/biom10020226 - 3 Feb 2020
Cited by 8 | Viewed by 2763
Abstract
Nicotinic acetylcholine receptors of α7 subtype (α7 nAChRs) are involved in regulating neuroinflammation and cognitive functions. Correspondingly, α7-/- mice demonstrate pro-inflammatory phenotype and impaired episodic memory. In addition, nAChRs expressed in mitochondria regulate the release of pro-apoptotic factors like cytochrome c. Here we [...] Read more.
Nicotinic acetylcholine receptors of α7 subtype (α7 nAChRs) are involved in regulating neuroinflammation and cognitive functions. Correspondingly, α7-/- mice demonstrate pro-inflammatory phenotype and impaired episodic memory. In addition, nAChRs expressed in mitochondria regulate the release of pro-apoptotic factors like cytochrome c. Here we studied whether the cognitive deficiency of α7-/- mice can be cured by oral consumption of either nicotine or N-stearoylethanolamine (NSE), a lipid possessing anti-inflammatory, cannabimimetic and membrane-stabilizing activity. Mice were examined in Novel Object Recognition behavioral test, their blood, brains and brain mitochondria were tested for the levels of interleukin-6, various nAChR subtypes and cytochrome c released by ELISA. The data presented demonstrate that both substances stimulated the raise of interleukin-6 in the blood and improved episodic memory of α7-/- mice. However, NSE improved, while nicotine worsened the brain mitochondria sustainability to apoptogenic stimuli, as shown by either decreased or increased amounts of cytochrome c released. Both nicotine and NSE up-regulated α4β2 nAChRs in the brain; NSE up-regulated, while nicotine down-regulated α9-containing nAChRs in the brain mitochondria. It is concluded that the level of alternative nAChR subtypes in the brain is critically important for memory and mitochondria sustainability in the absence of α7 nAChRs. Full article
(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data)
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17 pages, 2620 KiB  
Article
Attenuation in Nicotinic Acetylcholine Receptor α9 and α10 Subunit Double Knock-Out Mice of Experimental Autoimmune Encephalomyelitis
by Qiang Liu, Minshu Li, Paul Whiteaker, Fu-Dong Shi, Barbara J. Morley and Ronald J. Lukas
Biomolecules 2019, 9(12), 827; https://doi.org/10.3390/biom9120827 - 4 Dec 2019
Cited by 19 | Viewed by 3344
Abstract
Experimental autoimmune encephalomyelitis (EAE) is attenuated in nicotinic acetylcholine receptor (nAChR) α9 subunit knock-out (α9 KO) mice. However, protection is incomplete, raising questions about roles for related, nAChR α10 subunits in ionotropic or recently-revealed metabotropic contributions to effects. Here, we demonstrate reduced EAE [...] Read more.
Experimental autoimmune encephalomyelitis (EAE) is attenuated in nicotinic acetylcholine receptor (nAChR) α9 subunit knock-out (α9 KO) mice. However, protection is incomplete, raising questions about roles for related, nAChR α10 subunits in ionotropic or recently-revealed metabotropic contributions to effects. Here, we demonstrate reduced EAE severity and delayed onset of disease signs in nAChR α9/α10 subunit double knock-out (DKO) animals relative to effects in wild-type (WT) control mice. These effects are indistinguishable from contemporaneously-observed effects in nicotine-treated WT or in α9 KO mice. Immune cell infiltration into the spinal cord and brain, reactive oxygen species levels in vivo, and demyelination, mostly in the spinal cord, are reduced in DKO mice. Disease severity is not altered relative to WT controls in mice harboring a gain-of-function mutation in α9 subunits. These findings minimize the likelihood that additional deletion of nAChR α10 subunits impacts disease differently than α9 KO alone, whether through ionotropic, metabotropic, or alternative mechanisms. Moreover, our results provide further evidence of disease-exacerbating roles for nAChR containing α9 subunits (α9*-nAChR) in EAE inflammatory and autoimmune responses. This supports our hypothesis that α9*-nAChR or their downstream mediators are attractive targets for attenuation of inflammation and autoimmunity. Full article
(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data)
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Review

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15 pages, 2998 KiB  
Review
Discovery of the First Neurotransmitter Receptor: The Acetylcholine Nicotinic Receptor
by Jean-Pierre Changeux
Biomolecules 2020, 10(4), 547; https://doi.org/10.3390/biom10040547 - 3 Apr 2020
Cited by 38 | Viewed by 7812
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data)
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16 pages, 2665 KiB  
Review
Current Advances in Allosteric Modulation of Muscarinic Receptors
by Jan Jakubik and Esam E. El-Fakahany
Biomolecules 2020, 10(2), 325; https://doi.org/10.3390/biom10020325 - 18 Feb 2020
Cited by 30 | Viewed by 6075
Abstract
Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated [...] Read more.
Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic, and internal diseases like schizophrenia, Alzheimer’s disease, Huntington disease, type 2 diabetes, or chronic pulmonary obstruction. Here, we reviewed the progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation, and in vivo actions in order to understand the translational impact of studying this important class of pharmacological agents. We overviewed newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents. Full article
(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data)
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