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102nd Anniversary of Neurotransmitter Discovery: Cholinergic Pathways in Physiology and Pathophysiology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 October 2024 | Viewed by 5038

Special Issue Editor


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Guest Editor
Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institute, 14183 Huddinge, Sweden
Interests: nerve growth factor; neurotrophins; Alzheimer’s disease; therapy; encapsulated cell biodelivery
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Special Issue Information

Dear Colleagues,

The discovery of chemical synaptic transmission by Otto Loewi in 1921, and the further identification of acetylcholine as the first chemical moiety by Sir Hallett Dale, paved the way for an early understanding of the role of chemical messengers (termed neurotransmitters) in neurotransmission. These findings led to further discoveries of other chemical neurotransmitters and provided a new outlook on neuromodulation, as well as enhanced knowledge about the intricate network of signalling partners and specific receptors that make each neurotransmitter system unique. Acetylcholine, the primary modulator of the parasympathetic nervous system, was specifically shown to modulate neuromuscular junctions, inflammatory processes, blood vessel dilation, and glandular secretions, amongst others. The modulation of acetylcholine levels has been associated with pathological conditions, which makes it a noteworthy neurotransmitter to study in the context of human health.

This Special Issue invites recent advances on the role of acetylcholine in various aspects of physiological or pathological conditions.

Dr. Sumonto Mitra
Guest Editor

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Keywords

  • acetylcholine
  • physiological functions
  • pathological alterations
  • cholinergic pathways

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Published Papers (4 papers)

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Research

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24 pages, 4026 KiB  
Article
Modulation of the p75NTR during Adolescent Alcohol Exposure Prevents Cholinergic Neuronal Atrophy and Associated Acetylcholine Activity and Behavioral Dysfunction
by Brian T. Kipp and Lisa M. Savage
Int. J. Mol. Sci. 2024, 25(11), 5792; https://doi.org/10.3390/ijms25115792 - 26 May 2024
Cited by 1 | Viewed by 573
Abstract
Binge alcohol consumption during adolescence can produce lasting deficits in learning and memory while also increasing the susceptibility to substance use disorders. The adolescent intermittent ethanol (AIE) rodent model mimics human adolescent binge drinking and has identified the nucleus basalis magnocellularis (NbM) as [...] Read more.
Binge alcohol consumption during adolescence can produce lasting deficits in learning and memory while also increasing the susceptibility to substance use disorders. The adolescent intermittent ethanol (AIE) rodent model mimics human adolescent binge drinking and has identified the nucleus basalis magnocellularis (NbM) as a key site of pathology. The NbM is a critical regulator of prefrontal cortical (PFC) cholinergic function and attention. The cholinergic phenotype is controlled pro/mature neurotrophin receptor activation. We sought to determine if p75NTR activity contributes to the loss of cholinergic phenotype in AIE by using a p75NTR modulator (LM11A-31) to inhibit prodegenerative signaling during ethanol exposure. Male and female rats underwent 5 g/kg ethanol (AIE) or water (CON) exposure following 2-day-on 2-day-off cycles from postnatal day 25–57. A subset of these groups also received a protective dose of LM11A-31 (50 mg/kg) during adolescence. Rats were trained on a sustained attention task (SAT) and behaviorally relevant acetylcholine (ACh) activity was recorded in the PFC with a fluorescent indicator (AChGRAB 3.0). AIE produced learning deficits on the SAT, which were spared with LM11A-31. In addition, PFC ACh activity was blunted by AIE, which LM11A-31 corrected. Investigation of NbM ChAT+ and TrkA+ neuronal expression found that AIE led to a reduction of ChAT+TrkA+ neurons, which again LM11A-31 protected. Taken together, these findings demonstrate the p75NTR activity during AIE treatment is a key regulator of cholinergic degeneration. Full article
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Review

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25 pages, 1953 KiB  
Review
Cholinergic Mechanisms in Gastrointestinal Neoplasia
by Natalia Sampaio Moura, Alyssa Schledwitz, Madeline Alizadeh, Asha Kodan, Lea-Pearl Njei and Jean-Pierre Raufman
Int. J. Mol. Sci. 2024, 25(10), 5316; https://doi.org/10.3390/ijms25105316 - 13 May 2024
Cited by 1 | Viewed by 1006
Abstract
Acetylcholine-activated receptors are divided broadly into two major structurally distinct classes: ligand-gated ion channel nicotinic and G-protein-coupled muscarinic receptors. Each class encompasses several structurally related receptor subtypes with distinct patterns of tissue expression and post-receptor signal transduction mechanisms. The activation of both nicotinic [...] Read more.
Acetylcholine-activated receptors are divided broadly into two major structurally distinct classes: ligand-gated ion channel nicotinic and G-protein-coupled muscarinic receptors. Each class encompasses several structurally related receptor subtypes with distinct patterns of tissue expression and post-receptor signal transduction mechanisms. The activation of both nicotinic and muscarinic cholinergic receptors has been associated with the induction and progression of gastrointestinal neoplasia. Herein, after briefly reviewing the classification of acetylcholine-activated receptors and the role that nicotinic and muscarinic cholinergic signaling plays in normal digestive function, we consider the mechanics of acetylcholine synthesis and release by neuronal and non-neuronal cells in the gastrointestinal microenvironment, and current methodology and challenges in measuring serum and tissue acetylcholine levels accurately. Then, we critically evaluate the evidence that constitutive and ligand-induced activation of acetylcholine-activated receptors plays a role in promoting gastrointestinal neoplasia. We focus primarily on adenocarcinomas of the stomach, pancreas, and colon, because these cancers are particularly common worldwide and, when diagnosed at an advanced stage, are associated with very high rates of morbidity and mortality. Throughout this comprehensive review, we concentrate on identifying novel ways to leverage these observations for prognostic and therapeutic purposes. Full article
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18 pages, 5943 KiB  
Review
Contributions of Non-Neuronal Cholinergic Systems to the Regulation of Immune Cell Function, Highlighting the Role of α7 Nicotinic Acetylcholine Receptors
by Koichiro Kawashima, Masato Mashimo, Atsuo Nomura and Takeshi Fujii
Int. J. Mol. Sci. 2024, 25(8), 4564; https://doi.org/10.3390/ijms25084564 - 22 Apr 2024
Cited by 1 | Viewed by 1183
Abstract
Loewi’s discovery of acetylcholine (ACh) release from the frog vagus nerve and the discovery by Dale and Dudley of ACh in ox spleen led to the demonstration of chemical transmission of nerve impulses. ACh is now well-known to function as a neurotransmitter. However, [...] Read more.
Loewi’s discovery of acetylcholine (ACh) release from the frog vagus nerve and the discovery by Dale and Dudley of ACh in ox spleen led to the demonstration of chemical transmission of nerve impulses. ACh is now well-known to function as a neurotransmitter. However, advances in the techniques for ACh detection have led to its discovery in many lifeforms lacking a nervous system, including eubacteria, archaea, fungi, and plants. Notably, mRNAs encoding choline acetyltransferase and muscarinic and nicotinic ACh receptors (nAChRs) have been found in uninnervated mammalian cells, including immune cells, keratinocytes, vascular endothelial cells, cardiac myocytes, respiratory, and digestive epithelial cells. It thus appears that non-neuronal cholinergic systems are expressed in a variety of mammalian cells, and that ACh should now be recognized not only as a neurotransmitter, but also as a local regulator of non-neuronal cholinergic systems. Here, we discuss the role of non-neuronal cholinergic systems, with a focus on immune cells. A current focus of much research on non-neuronal cholinergic systems in immune cells is α7 nAChRs, as these receptors expressed on macrophages and T cells are involved in regulating inflammatory and immune responses. This makes α7 nAChRs an attractive potential therapeutic target. Full article
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0 pages, 1615 KiB  
Review
Nicotinic Receptors in Human Chromaffin Cells: Characterization, Functional and Physical Interactions between Subtypes and Regulation
by Amanda Jiménez-Pompa and Almudena Albillos
Int. J. Mol. Sci. 2024, 25(4), 2304; https://doi.org/10.3390/ijms25042304 - 15 Feb 2024
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Abstract
This review summarizes our research on nicotinic acetylcholine receptors in human chromaffin cells. Limited research has been conducted in this field on human tissue, primarily due to the difficulties associated with obtaining human cells. Receptor subtypes were characterized here using molecular biology and [...] Read more.
This review summarizes our research on nicotinic acetylcholine receptors in human chromaffin cells. Limited research has been conducted in this field on human tissue, primarily due to the difficulties associated with obtaining human cells. Receptor subtypes were characterized here using molecular biology and electrophysiological patch-clamp techniques. However, the most significant aspect of this study refers to the cross-talk between the two main subtypes identified in these cells, the α7- and α3β4* subtypes, aiming to avoid their desensitization. The article also reviews other aspects, including the regulation of their expression, function or physical interaction by choline, Ca2+, and tyrosine and serine/threonine phosphatases. Additionally, the influence of sex on their expression is also discussed. Full article
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