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Cholinergic Signaling in Human Health and Diseases
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Cholinergic Signaling in Human Health and Diseases

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

Deadline for manuscript submissions: closed (20 December 2020) | Viewed by 41598

Special Issue Editor

Dr. Toshio Takahashi

E-Mail Website
Guest Editor
Suntory Foundation for Life Sciences, Bioorganic Research Institute, Kyoto 619-0284, Japan
Interests: intestinal organoid; stem cell; signaling; non-neuronal acetylcholine; acetylcholine receptor
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is now well-established that acetylcholine (ACh) and its receptors (nicotinic and muscarinic receptors (n- and mAChRs)) as important constituents of the cholinergic system are ubiquitous molecules in life. Other components of the cholinergic system (choline acetyltransferase (ChAT), choline transporter (ChT), and acetylcholinesterase (AChE)) have also been demonstrated in mammalian non-neuronal cells, including those of humans. The traditional view of ACh regards it as a neurotransmitter. In addition to neurotransmission, ACh plays important roles in various aspects of cell biology and homeostasis outside of the nervous system. ACh is actually synthesized by all live cells and plays an intermediary role in the interactions of non-neuronal cells with the external environment, endocrine hormones, growth factors, cytokines, and the central nervous system. Thus, cholinergic signaling in non-neuronal cells is comparable to neuronal cholinergic signaling. In addition to improving our understanding of the structure and function of the cholinergic system, significant progress has also been made in elucidating the roles of neuronal and non-neuronal ACh in the pathogenesis and treatment of human disease. This Issue will explore new insights into how cholinergic signaling functions in mammals, how its roles contribute to protecting the body from disease, and how the molecules can be manipulated to treat disease.

Dr. Toshio Takahashi
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • neuron
  • immune cell
  • stem cell
  • signaling
  • acetylcholine (ACh)
  • non-neuronal ACh
  • acetylcholine receptor
  • acetylcholine receptor to muscarinic ACh receptor
  • nicotinic ACh receptor

Published Papers (7 papers)

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Research

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22 pages, 5739 KiB  
Article
Neither Excessive Nitric Oxide Accumulation nor Acute Hyperglycemia Affects the N-Acetylaspartate Network in Wistar Rat Brain Cells
by Marlena Zyśk, Piotr Pikul, Robert Kowalski, Krzysztof Lewandowski, Monika Sakowicz-Burkiewicz and Tadeusz Pawełczyk
Int. J. Mol. Sci. 2020, 21(22), 8541; https://doi.org/10.3390/ijms21228541 - 12 Nov 2020
Cited by 4 | Viewed by 2353
Abstract
The N-acetylaspartate network begins in neurons with N-acetylaspartate production catalyzed by aspartate N-acetyltransferase from acetyl-CoA and aspartate. Clinical studies reported a significant depletion in N-acetylaspartate brain level in type 1 diabetic patients. The main goal of this study was [...] Read more.
The N-acetylaspartate network begins in neurons with N-acetylaspartate production catalyzed by aspartate N-acetyltransferase from acetyl-CoA and aspartate. Clinical studies reported a significant depletion in N-acetylaspartate brain level in type 1 diabetic patients. The main goal of this study was to establish the impact of either hyperglycemia or oxidative stress on the N-acetylaspartate network. For the in vitro part of the study, embryonic rat primary neurons were treated by using a nitric oxide generator for 24 h followed by 6 days of post-treatment culture, while the neural stem cells were cultured in media with 25–75 mM glucose. For the in vivo part, male adult Wistar rats were injected with streptozotocin (65 mg/kg body weight, ip) to induce hyperglycemia (diabetes model) and euthanized 2 or 8 weeks later. Finally, the biochemical profile, NAT8L protein/Nat8l mRNA levels and enzymatic activity were analyzed. Ongoing oxidative stress processes significantly affected energy metabolism and cholinergic neurotransmission. However, the applied factors did not affect the N-acetylaspartate network. This study shows that reduced N-acetylaspartate level in type 1 diabetes is not related to oxidative stress and that does not trigger N-acetylaspartate network fragility. To reveal why N-acetylaspartate is reduced in this pathology, other processes should be considered. Full article
(This article belongs to the Special Issue Cholinergic Signaling in Human Health and Diseases)
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Review

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18 pages, 1507 KiB  
Review
Regulation of Immune Functions by Non-Neuronal Acetylcholine (ACh) via Muscarinic and Nicotinic ACh Receptors
by Masato Mashimo, Yasuhiro Moriwaki, Hidemi Misawa, Koichiro Kawashima and Takeshi Fujii
Int. J. Mol. Sci. 2021, 22(13), 6818; https://doi.org/10.3390/ijms22136818 - 24 Jun 2021
Cited by 23 | Viewed by 4138
Abstract
Acetylcholine (ACh) is the classical neurotransmitter in the cholinergic nervous system. However, ACh is now known to regulate various immune cell functions. In fact, T cells, B cells, and macrophages all express components of the cholinergic system, including ACh, muscarinic, and nicotinic ACh [...] Read more.
Acetylcholine (ACh) is the classical neurotransmitter in the cholinergic nervous system. However, ACh is now known to regulate various immune cell functions. In fact, T cells, B cells, and macrophages all express components of the cholinergic system, including ACh, muscarinic, and nicotinic ACh receptors (mAChRs and nAChRs), choline acetyltransferase, acetylcholinesterase, and choline transporters. In this review, we will discuss the actions of ACh in the immune system. We will first briefly describe the mechanisms by which ACh is stored in and released from immune cells. We will then address Ca2+ signaling pathways activated via mAChRs and nAChRs on T cells and B cells, highlighting the importance of ACh for the function of T cells, B cells, and macrophages, as well as its impact on innate and acquired (cellular and humoral) immunity. Lastly, we will discuss the effects of two peptide ligands, secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) and hippocampal cholinergic neurostimulating peptide (HCNP), on cholinergic activity in T cells. Overall, we stress the fact that ACh does not function only as a neurotransmitter; it impacts immunity by exerting diverse effects on immune cells via mAChRs and nAChRs. Full article
(This article belongs to the Special Issue Cholinergic Signaling in Human Health and Diseases)
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14 pages, 1123 KiB  
Review
Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology
by Bisei Ohkawara, Mikako Ito and Kinji Ohno
Int. J. Mol. Sci. 2021, 22(5), 2455; https://doi.org/10.3390/ijms22052455 - 28 Feb 2021
Cited by 19 | Viewed by 9109
Abstract
Signal transduction at the neuromuscular junction (NMJ) is affected in many human diseases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert–Eaton myasthenic syndrome, Isaacs’ syndrome, Schwartz–Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse [...] Read more.
Signal transduction at the neuromuscular junction (NMJ) is affected in many human diseases, including congenital myasthenic syndromes (CMS), myasthenia gravis, Lambert–Eaton myasthenic syndrome, Isaacs’ syndrome, Schwartz–Jampel syndrome, Fukuyama-type congenital muscular dystrophy, amyotrophic lateral sclerosis, and sarcopenia. The NMJ is a prototypic cholinergic synapse between the motor neuron and the skeletal muscle. Synaptogenesis of the NMJ has been extensively studied, which has also been extrapolated to further understand synapse formation in the central nervous system. Studies of genetically engineered mice have disclosed crucial roles of secreted molecules in the development and maintenance of the NMJ. In this review, we focus on the secreted signaling molecules which regulate the clustering of acetylcholine receptors (AChRs) at the NMJ. We first discuss the signaling pathway comprised of neural agrin and its receptors, low-density lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK). This pathway drives the clustering of acetylcholine receptors (AChRs) to ensure efficient signal transduction at the NMJ. We also discuss three secreted molecules (Rspo2, Fgf18, and connective tissue growth factor (Ctgf)) that we recently identified in the Wnt/β-catenin and fibroblast growth factors (FGF) signaling pathways. The three secreted molecules facilitate the clustering of AChRs by enhancing the agrin-Lrp4-MuSK signaling pathway. Full article
(This article belongs to the Special Issue Cholinergic Signaling in Human Health and Diseases)
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24 pages, 1551 KiB  
Review
Functions of Muscarinic Receptor Subtypes in Gastrointestinal Smooth Muscle: A Review of Studies with Receptor-Knockout Mice
by Yasuyuki Tanahashi, Seiichi Komori, Hayato Matsuyama, Takio Kitazawa and Toshihiro Unno
Int. J. Mol. Sci. 2021, 22(2), 926; https://doi.org/10.3390/ijms22020926 - 18 Jan 2021
Cited by 31 | Viewed by 13538
Abstract
Parasympathetic signalling via muscarinic acetylcholine receptors (mAChRs) regulates gastrointestinal smooth muscle function. In most instances, the mAChR population in smooth muscle consists mainly of M2 and M3 subtypes in a roughly 80% to 20% mixture. Stimulation of these mAChRs triggers a [...] Read more.
Parasympathetic signalling via muscarinic acetylcholine receptors (mAChRs) regulates gastrointestinal smooth muscle function. In most instances, the mAChR population in smooth muscle consists mainly of M2 and M3 subtypes in a roughly 80% to 20% mixture. Stimulation of these mAChRs triggers a complex array of biochemical and electrical events in the cell via associated G proteins, leading to smooth muscle contraction and facilitating gastrointestinal motility. Major signalling events induced by mAChRs include adenylyl cyclase inhibition, phosphoinositide hydrolysis, intracellular Ca2+ mobilisation, myofilament Ca2+ sensitisation, generation of non-selective cationic and chloride currents, K+ current modulation, inhibition or potentiation of voltage-dependent Ca2+ currents and membrane depolarisation. A lack of ligands with a high degree of receptor subtype selectivity and the frequent contribution of multiple receptor subtypes to responses in the same cell type have hampered studies on the signal transduction mechanisms and functions of individual mAChR subtypes. Therefore, novel strategies such as genetic manipulation are required to elucidate both the contributions of specific AChR subtypes to smooth muscle function and the underlying molecular mechanisms. In this article, we review recent studies on muscarinic function in gastrointestinal smooth muscle using mAChR subtype-knockout mice. Full article
(This article belongs to the Special Issue Cholinergic Signaling in Human Health and Diseases)
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15 pages, 612 KiB  
Review
Overcoming Obstacles to Targeting Muscarinic Receptor Signaling in Colorectal Cancer
by Osman Ali, Mazen Tolaymat, Shien Hu, Guofeng Xie and Jean-Pierre Raufman
Int. J. Mol. Sci. 2021, 22(2), 716; https://doi.org/10.3390/ijms22020716 - 13 Jan 2021
Cited by 9 | Viewed by 5355
Abstract
Despite great advances in our understanding of the pathobiology of colorectal cancer and the genetic and environmental factors that mitigate its onset and progression, a paucity of effective treatments persists. The five-year survival for advanced, stage IV disease remains substantially less than 20%. [...] Read more.
Despite great advances in our understanding of the pathobiology of colorectal cancer and the genetic and environmental factors that mitigate its onset and progression, a paucity of effective treatments persists. The five-year survival for advanced, stage IV disease remains substantially less than 20%. This review examines a relatively untapped reservoir of potential therapies to target muscarinic receptor expression, activation, and signaling in colorectal cancer. Most colorectal cancers overexpress M3 muscarinic receptors (M3R), and both in vitro and in vivo studies have shown that activating these receptors stimulates cellular programs that result in colon cancer growth, survival, and spread. In vivo studies using mouse models of intestinal neoplasia have shown that using either genetic or pharmacological approaches to block M3R expression and activation, respectively, attenuates the development and progression of colon cancer. Moreover, both in vitro and in vivo studies have shown that blocking the activity of matrix metalloproteinases (MMPs) that are induced selectively by M3R activation, i.e., MMP1 and MMP7, also impedes colon cancer growth and progression. Nonetheless, the widespread expression of muscarinic receptors and MMPs and their importance for many cellular functions raises important concerns about off-target effects and the safety of employing similar strategies in humans. As we highlight in this review, highly selective approaches can overcome these obstacles and permit clinicians to exploit the reliance of colon cancer cells on muscarinic receptors and their downstream signal transduction pathways for therapeutic purposes. Full article
(This article belongs to the Special Issue Cholinergic Signaling in Human Health and Diseases)
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16 pages, 2039 KiB  
Review
Multiple Roles for Cholinergic Signaling from the Perspective of Stem Cell Function
by Toshio Takahashi
Int. J. Mol. Sci. 2021, 22(2), 666; https://doi.org/10.3390/ijms22020666 - 11 Jan 2021
Cited by 7 | Viewed by 3978
Abstract
Stem cells have extensive proliferative potential and the ability to differentiate into one or more mature cell types. The mechanisms by which stem cells accomplish self-renewal provide fundamental insight into the origin and design of multicellular organisms. These pathways allow the repair of [...] Read more.
Stem cells have extensive proliferative potential and the ability to differentiate into one or more mature cell types. The mechanisms by which stem cells accomplish self-renewal provide fundamental insight into the origin and design of multicellular organisms. These pathways allow the repair of damage and extend organismal life beyond that of component cells, and they probably preceded the evolution of complex metazoans. Understanding the true nature of stem cells can only come from discovering how they are regulated. The concept that stem cells are controlled by particular microenvironments, also known as niches, has been widely accepted. Technical advances now allow characterization of the zones that maintain and control stem cell activity in several organs, including the brain, skin, and gut. Cholinergic neurons release acetylcholine (ACh) that mediates chemical transmission via ACh receptors such as nicotinic and muscarinic receptors. Although the cholinergic system is composed of organized nerve cells, the system is also involved in mammalian non-neuronal cells, including stem cells, embryonic stem cells, epithelial cells, and endothelial cells. Thus, cholinergic signaling plays a pivotal role in controlling their behaviors. Studies regarding this signal are beginning to unify our understanding of stem cell regulation at the cellular and molecular levels, and they are expected to advance efforts to control stem cells therapeutically. The present article reviews recent findings about cholinergic signaling that is essential to control stem cell function in a cholinergic niche. Full article
(This article belongs to the Special Issue Cholinergic Signaling in Human Health and Diseases)
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14 pages, 6472 KiB  
Review
Characteristic Effects of the Cardiac Non-Neuronal Acetylcholine System Augmentation on Brain Functions
by Yoshihiko Kakinuma
Int. J. Mol. Sci. 2021, 22(2), 545; https://doi.org/10.3390/ijms22020545 - 07 Jan 2021
Cited by 5 | Viewed by 2270
Abstract
Since the discovery of non-neuronal acetylcholine in the heart, this specific system has drawn scientific interest from many research fields, including cardiology, immunology, and pharmacology. This system, acquired by cardiomyocytes independent of the parasympathetic nervous system of the autonomic nervous system, helps us [...] Read more.
Since the discovery of non-neuronal acetylcholine in the heart, this specific system has drawn scientific interest from many research fields, including cardiology, immunology, and pharmacology. This system, acquired by cardiomyocytes independent of the parasympathetic nervous system of the autonomic nervous system, helps us to understand unsolved issues in cardiac physiology and to realize that the system may be more pivotal for cardiac homeostasis than expected. However, it has been shown that the effects of this system may not be restricted to the heart, but rather extended to cover extra-cardiac organs. To this end, this system intriguingly influences brain function, specifically potentiating blood brain barrier function. Although the results reported appear to be unusual, this novel characteristic can provide us with another research interest and therapeutic application mode for central nervous system diseases. In this review, we discuss our recent studies and raise the possibility of application of this system as an adjunctive therapeutic modality. Full article
(This article belongs to the Special Issue Cholinergic Signaling in Human Health and Diseases)
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