Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.4
4.2
Journals
Molecules
Special Issues
Molecular Partners in the Structure and Function of Nicotinic Acetylcholine...
molecules-logo
Submit to Molecules Review for Molecules Propose a Special Issue

Journal Menu

► Journal Menu

Journal Browser

► Journal Browser
share announcement

Molecular Partners in the Structure and Function of Nicotinic Acetylcholine Receptors

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Molecular Structure".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 23940

Special Issue Editor

Prof. Dr. Roger L. Papke

E-Mail Website
Guest Editor
Department of Pharmacology and Therapeutics, University of Florida School of Medicine, Gainesville, FL 32610, USA
Interests: alpha7 nAChR; addiction; electrophysiology; pharmacology; inflammation; allosteric ligands; molecular and kinetic modeling

Special Issue Information

Dear Colleagues,

Nicotinic acetylcholine receptors (nAChR) are the primary mediators of fast synaptic transmission outside the central nervous system; they are also important modulators of synaptic function in the brain for cognitive function and motivated behavior. Each receptor comprises a complex of five related protein subunits—molecular partners—each with subdomains that make specialized contacts with other molecular partners, ligands, or other proteins that regulate receptor function or expression. This Special Issue will address the diversity, structures, and molecular dynamics of nAChR in addition to how ligands regulate conformational transitions of the receptors, and how specific proteins chaperone the different receptors to serve specific functions in diverse tissues.

Prof. Roger L. Papke
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • receptor polymorphisms
  • subunit diversity and structures
  • orthosteric steric activation and coupling
  • protein partners in receptor trafficking and localization
  • allosteric mechanisms of nAChR

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (7 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

11 pages, 1622 KiB  
Article
Rare Missense Variants of the Human β4 Subunit Alter Nicotinic α3β4 Receptor Plasma Membrane Localisation
by Sara Francesca Colombo, Cecilia Galli, Arianna Crespi, Massimiliano Renzi and Cecilia Gotti
Molecules 2023, 28(3), 1247; https://doi.org/10.3390/molecules28031247 - 27 Jan 2023
Cited by 2 | Viewed by 1565
Abstract
α3β4 nicotinic acetylcholine receptors (nARs) are pentameric ligand-gated cation channels that function in peripheral tissue and in the peripheral and central nervous systems, where they are critical mediators of ganglionic synaptic transmission and modulators of reward-related behaviours. In the pentamer, two α3β4 subunit [...] Read more.
α3β4 nicotinic acetylcholine receptors (nARs) are pentameric ligand-gated cation channels that function in peripheral tissue and in the peripheral and central nervous systems, where they are critical mediators of ganglionic synaptic transmission and modulators of reward-related behaviours. In the pentamer, two α3β4 subunit couples provide ligand-binding sites, and the fifth single (accessory) subunit (α3 or β4) regulates receptor trafficking from the endoplasmic reticulum to the cell surface. A number of rare missense variants of the human β4 subunit have recently been linked to nicotine dependence and/or sporadic amyotrophic lateral sclerosis, and altered responses to nicotine have been reported for these variants; however, it is unknown whether the effects of mutations depend on the subunit within the ligand-binding couples and/or on the fifth subunit. Here, by expressing single populations of pentameric receptors with fixed stoichiometry in cultured cells, we investigated the effect of β4 variants in the fifth position on the assembly and surface exposure of α3β4 nAChRs. The results demonstrate that the missense mutations in the accessory subunit alone, despite not affecting the assembly of α3β4 receptors, alter their trafficking and surface localisation. Thus, altered trafficking of an otherwise functional nAChR may underlie the pathogenic effects of these mutations. Full article
(This article belongs to the Special Issue Molecular Partners in the Structure and Function of Nicotinic Acetylcholine Receptors)
►▼ Show Figures

Figure 1

16 pages, 2854 KiB  
Article
Structural Insights into the Role of β3 nAChR Subunit in the Activation of Nicotinic Receptors
by Petros Giastas, Athanasios Papakyriakou, George Tsafaras, Socrates J. Tzartos and Marios Zouridakis
Molecules 2022, 27(14), 4642; https://doi.org/10.3390/molecules27144642 - 20 Jul 2022
Cited by 1 | Viewed by 2415
Abstract
The β3 subunit of nicotinic acetylcholine receptors (nAChRs) participates in heteropentameric assemblies with some α and other β neuronal subunits forming a plethora of various subtypes, differing in their electrophysiological and pharmacological properties. While β3 has for several years been considered an accessory [...] Read more.
The β3 subunit of nicotinic acetylcholine receptors (nAChRs) participates in heteropentameric assemblies with some α and other β neuronal subunits forming a plethora of various subtypes, differing in their electrophysiological and pharmacological properties. While β3 has for several years been considered an accessory subunit without direct participation in the formation of functional binding sites, recent electrophysiology data have disputed this notion and indicated the presence of a functional (+) side on the extracellular domain (ECD) of β3. In this study, we present the 2.4 Å resolution crystal structure of the monomeric β3 ECD, which revealed rather distinctive loop C features as compared to those of α nAChR subunits, leading to intramolecular stereochemical hindrance of the binding site cavity. Vigorous molecular dynamics simulations in the context of full length pentameric β3-containing nAChRs, while not excluding the possibility of a β3 (+) binding site, demonstrate that this site cannot efficiently accommodate the agonist nicotine. From the structural perspective, our results endorse the accessory rather than functional role of the β3 nAChR subunit, in accordance with earlier functional studies on β3-containing nAChRs. Full article
(This article belongs to the Special Issue Molecular Partners in the Structure and Function of Nicotinic Acetylcholine Receptors)
►▼ Show Figures

Figure 1

14 pages, 2770 KiB  
Article
Sulfonium Ligands of the α7 nAChR
by Nicole A. Horenstein, Clare Stokes and Roger L. Papke
Molecules 2021, 26(18), 5643; https://doi.org/10.3390/molecules26185643 - 17 Sep 2021
Cited by 3 | Viewed by 2401
Abstract
The α7 nicotinic acetylcholine receptor (nAChR) is an important target given its role in cognitive function as well as in the cholinergic anti-inflammatory pathway, where ligands that are effective at stabilizing desensitized states of the receptor are of particular interest. The typical structural [...] Read more.
The α7 nicotinic acetylcholine receptor (nAChR) is an important target given its role in cognitive function as well as in the cholinergic anti-inflammatory pathway, where ligands that are effective at stabilizing desensitized states of the receptor are of particular interest. The typical structural element associated with a good desensitizer is the ammonium pharmacophore, but recent work has identified that a trivalent sulfur, in the positively charged sulfonium form, can substitute for the nitrogen in the ammonium pharmacophore. However, the breadth and scope of employing the sulfonium group is largely unexplored. In this work, we have surveyed a disparate group of sulfonium compounds for their functional activity with α7 as well as other nAChR subtypes. Amongst them, we found that there is a wide range of ability to induce α7 desensitization, with 4-hydroxyphenyldimethylsulfonium and suplatast sulfonium salts being the most desensitizing. The smallest sulfonium compound, trimethylsulfonium, was a partial agonist for α7 and other neuronal nAChR. Molecular docking into the α7 receptor extracellular domain revealed preferred poses in the orthosteric binding site for all but one compound, with typical cation–pi interactions as seen with traditional ammonium compounds. A number of the compounds tested may serve as useful platforms for further development of α7 desensitizing ability and for receptor subtype selectivity. Full article
(This article belongs to the Special Issue Molecular Partners in the Structure and Function of Nicotinic Acetylcholine Receptors)
►▼ Show Figures

Graphical abstract

Review

Jump to: Research

26 pages, 8242 KiB  
Review
Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly
by Ralph H. Loring
Molecules 2022, 27(14), 4527; https://doi.org/10.3390/molecules27144527 - 15 Jul 2022
Cited by 8 | Viewed by 3359
Abstract
The process of how multimeric transmembrane proteins fold and assemble in the endoplasmic reticulum is not well understood. The alpha7 nicotinic receptor (α7 nAChR) is a good model for multimeric protein assembly since it has at least two independent and specialized chaperones: Resistance [...] Read more.
The process of how multimeric transmembrane proteins fold and assemble in the endoplasmic reticulum is not well understood. The alpha7 nicotinic receptor (α7 nAChR) is a good model for multimeric protein assembly since it has at least two independent and specialized chaperones: Resistance to Inhibitors of Cholinesterase 3 (RIC-3) and Nicotinic Acetylcholine Receptor Regulator (NACHO). Recent cryo-EM and NMR data revealed structural features of α7 nAChRs. A ser-ala-pro (SAP) motif precedes a structurally important but unique “latch” helix in α7 nAChRs. A sampling of α7 sequences suggests the SAP motif is conserved from C. elegans to humans, but the latch sequence is only conserved in vertebrates. How RIC-3 and NACHO facilitate receptor subunits folding into their final pentameric configuration is not known. The artificial intelligence program AlphaFold2 recently predicted structures for NACHO and RIC-3. NACHO is highly conserved in sequence and structure across species, but RIC-3 is not. This review ponders how different intrinsically disordered RIC-3 isoforms from C. elegans to humans interact with α7 nAChR subunits despite having little sequence homology across RIC-3 species. Two models from the literature about how RIC-3 assists α7 nAChR assembly are evaluated considering recent structural information about the receptor and its chaperones. Full article
(This article belongs to the Special Issue Molecular Partners in the Structure and Function of Nicotinic Acetylcholine Receptors)
►▼ Show Figures

Figure 1

17 pages, 910 KiB  
Review
Neuroinflammation Modulation via α7 Nicotinic Acetylcholine Receptor and Its Chaperone, RIC-3
by Tehila Mizrachi, Adi Vaknin-Dembinsky, Talma Brenner and Millet Treinin
Molecules 2021, 26(20), 6139; https://doi.org/10.3390/molecules26206139 - 11 Oct 2021
Cited by 28 | Viewed by 4782
Abstract
Nicotinic acetylcholine receptors (nAChRs) are widely expressed in or on various cell types and have diverse functions. In immune cells nAChRs regulate proliferation, differentiation and cytokine release. Specifically, activation of the α7 nAChR reduces inflammation as part of the cholinergic anti-inflammatory pathway. Here [...] Read more.
Nicotinic acetylcholine receptors (nAChRs) are widely expressed in or on various cell types and have diverse functions. In immune cells nAChRs regulate proliferation, differentiation and cytokine release. Specifically, activation of the α7 nAChR reduces inflammation as part of the cholinergic anti-inflammatory pathway. Here we review numerous effects of α7 nAChR activation on immune cell function and differentiation. Further, we also describe evidence implicating this receptor and its chaperone RIC-3 in diseases of the central nervous system and in neuroinflammation, focusing on multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Deregulated neuroinflammation due to dysfunction of α7 nAChR provides one explanation for involvement of this receptor and of RIC-3 in neurodegenerative diseases. In this review, we also provide evidence implicating α7 nAChRs and RIC-3 in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) involving neuroinflammation. Besides, we will describe the therapeutic implications of activating the cholinergic anti-inflammatory pathway for diseases involving neuroinflammation. Full article
(This article belongs to the Special Issue Molecular Partners in the Structure and Function of Nicotinic Acetylcholine Receptors)
►▼ Show Figures

Figure 1

27 pages, 2255 KiB  
Review
Pursuing High-Resolution Structures of Nicotinic Acetylcholine Receptors: Lessons Learned from Five Decades
by Manuel Delgado-Vélez, Orestes Quesada, Juan C. Villalobos-Santos, Rafael Maldonado-Hernández, Guillermo Asmar-Rovira, Raymond C. Stevens and José Antonio Lasalde-Dominicci
Molecules 2021, 26(19), 5753; https://doi.org/10.3390/molecules26195753 - 23 Sep 2021
Cited by 14 | Viewed by 4573
Abstract
Since their discovery, nicotinic acetylcholine receptors (nAChRs) have been extensively studied to understand their function, as well as the consequence of alterations leading to disease states. Importantly, these receptors represent pharmacological targets to treat a number of neurological and neurodegenerative disorders. Nevertheless, their [...] Read more.
Since their discovery, nicotinic acetylcholine receptors (nAChRs) have been extensively studied to understand their function, as well as the consequence of alterations leading to disease states. Importantly, these receptors represent pharmacological targets to treat a number of neurological and neurodegenerative disorders. Nevertheless, their therapeutic value has been limited by the absence of high-resolution structures that allow for the design of more specific and effective drugs. This article offers a comprehensive review of five decades of research pursuing high-resolution structures of nAChRs. We provide a historical perspective, from initial structural studies to the most recent X-ray and cryogenic electron microscopy (Cryo-EM) nAChR structures. We also discuss the most relevant structural features that emerged from these studies, as well as perspectives in the field. Full article
(This article belongs to the Special Issue Molecular Partners in the Structure and Function of Nicotinic Acetylcholine Receptors)
►▼ Show Figures

Figure 1

15 pages, 1908 KiB  
Review
An Inside Job: Molecular Determinants for Postsynaptic Localization of Nicotinic Acetylcholine Receptors
by Michael Ferns
Molecules 2021, 26(11), 3065; https://doi.org/10.3390/molecules26113065 - 21 May 2021
Cited by 5 | Viewed by 3643
Abstract
Nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic transmission at neuromuscular and autonomic ganglionic synapses in the peripheral nervous system. The postsynaptic localization of muscle ((α1)2β1γδ) and neuronal ((α3β4)2β4) nicotinic receptors at these synapses is mediated by interactions between the [...] Read more.
Nicotinic acetylcholine receptors (nAChRs) mediate fast synaptic transmission at neuromuscular and autonomic ganglionic synapses in the peripheral nervous system. The postsynaptic localization of muscle ((α1)2β1γδ) and neuronal ((α3β4)2β4) nicotinic receptors at these synapses is mediated by interactions between the nAChR intracellular domains and cytoplasmic scaffolding proteins. Recent high resolution structures and functional studies provide new insights into the molecular determinants that mediate these interactions. Surprisingly, they reveal that the muscle nAChR binds 1–3 rapsyn scaffolding molecules, which dimerize and thereby form an interconnected lattice between receptors. Moreover, rapsyn binds two distinct sites on the nAChR subunit cytoplasmic loops; the MA-helix on one or more subunits and a motif specific to the β subunit. Binding at the latter site is regulated by agrin-induced phosphorylation of βY390, and increases the stoichiometry of rapsyn/AChR complexes. Similarly, the neuronal nAChR may be localized at ganglionic synapses by phosphorylation-dependent interactions with 14-3-3 adaptor proteins which bind specific motifs in each of the α3 subunit cytoplasmic loops. Thus, postsynaptic localization of nAChRs is mediated by regulated interactions with multiple scaffolding molecules, and the stoichiometry of these complexes likely helps regulate the number, density, and stability of receptors at the synapse. Full article
(This article belongs to the Special Issue Molecular Partners in the Structure and Function of Nicotinic Acetylcholine Receptors)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-7
Back to TopTop