Acetylcholine (muscarinic)
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PROVIDER: S-EPMC2884600 | biostudies-literature | 2009 Nov
REPOSITORIES: biostudies-literature
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Project description:The M3 muscarinic acetylcholine receptor (CHRM3) is predominantly expressed in the basal epidermal layer where it mediates the effects of the auto/paracrine cytotransmitter acetylcholine. Patients with the autoimmune blistering disease pemphigus develop autoantibodies to CHRM3 and show alterations in keratinocyte adhesion, proliferation and differentiation, suggesting that CHRM3 controls these cellular functions. Chrm3 mice display altered epidermal morphology resembling that seen in patients with pemphigus vulgaris. Here, we characterized the cellular and molecular mechanisms whereby CHRM3 controls epidermal structure and function. We used single cell (sc)RNA-seq to evaluate keratinocyte heterogeneity and identify differentially expressed genes in specific subpopulations of epidermal cells in Chrm3 KO neonatal mice.
2022-05-06 | GSE201885 | GEO
Project description:Muscarinic acetylcholine receptor M3 (M3) and its downstream effector Gq/11 are critical drug development targets given their involvement in numerous physiological processes and diseases. Although a cryo-electron microscopy study previously defined the structure of the M3-miniGq complex, the lack of information on the intracellular loop 3 (ICL3) of M3 and α-helical domain (AHD) of Gαq has made it difficult to comprehend the molecular mechanism of M3-Gq coupling fully. Here, we present the molecular mechanism underlying the dynamic interactions between the wild-type full-length M3 and heterotrimeric Gq using hydrogen-deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cell systems. This study suggests potential binding interfaces between M3 and Gq in pre-assembled and fully active nucleotide-free complexes. In addition to well-known binding interfaces, we observed the interaction of long ICL3 with Gβγ. Furthermore, M3 ICL3 negatively affected M3-Gq coupling, and the Gαq AHD underwent unique conformational changes during M3-Gq coupling. Therefore, we propose a comprehensive molecular mechanism of M3-Gq coupling by analyzing previously well-defined binding interfaces and neglected regions, such as M3 ICL3 and the Gαq AHD.
2024-05-22 | PXD042562 | Pride
Project description:Muscarinic acetylcholine receptor-active compounds have potential for the treatment of Alzheimer's disease. In this study, a series of natural and synthetic flavones and flavonols was assayed in vitro for their ability to inhibit radioligand binding at human cloned M1 muscarinic receptors. Several compounds were found to possess competitive binding affinity (Ki=40-110 µM), comparable to that of acetylcholine (Ki=59 µM). Despite the fact that these compounds lack a positively-charged ammonium group under physiological conditions, molecular modelling studies suggested that they bind to the orthosteric site of the receptor, mainly through non-polar interactions.
| S-EPMC6270666 | biostudies-literature
Project description:In contrast to most peripheral tissues where multiple subtypes of muscarinic acetylcholine receptor (mAChR) coexist, with each of them playing its part in the orchestra of parasympathetic innervation, the myocardium has been traditionally considered to possess a single mAChR subtype. Although there is much evidence to support the notion that one receptor subtype (M2) orchestrates myocardial muscarinic transduction, there is emerging evidence that M1 and M3 receptors are also expressed and are of potential physiological, pathophysiological and pharmacological relevance. Clarifying this issue has a profound impact on our thinking about the cholinergic control of the heart function and disease and approaches to new drug development for the treatment of heart disease associated with parasympathetic dysfunction. This review article presents evidence for the presence of the M3 receptor subtype in the heart, and analyzes the controversial data from published pharmacological, functional and molecular studies. The potential roles of the M3 receptors, in parasympathetic control of heart function under normal physiological conditions and in heart failure, myocardial ischemia and arrhythmias, are discussed. On the basis of these considerations, we have made some proposals concerning the future of myocardial M3 receptor research.
| S-EPMC1574958 | biostudies-literature
Project description: Not available
| S-EPMC3980162 | biostudies-literature
Project description:Acetylcholine, the first neurotransmitter to be identified, exerts many of its physiological actions via activation of a family of G-protein-coupled receptors (GPCRs) known as muscarinic acetylcholine receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G-protein coupling preference and the physiological responses they mediate. Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences. We describe here the structure of the G(q/11)-coupled M3 mAChR ('M3 receptor', from rat) bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the G(i/o)-coupled M2 receptor, offers possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows a structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and provide additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.
| S-EPMC3529910 | biostudies-literature
Project description:Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the ?2 adrenergic receptor (?2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the ?2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.
| S-EPMC4020789 | biostudies-literature
Project description:The muscarinic cholinergic system regulates peripheral and central nervous system functions, and, thus, their potential as a therapeutic target for several neurodegenerative diseases is undoubted. A clinically applicable positron emission tomography (PET) tracer would facilitate the monitoring of disease progression, elucidate the role of muscarinic acetylcholine receptors (mAChR) in disease development and would aid to clarify the diverse natural functions of mAChR regulation throughout the nervous system, which still are largely unresolved. Still, no mAChR PET tracer has yet found broad clinical application, which demands mAChR tracers with improved imaging properties. This paper reviews strategies of mAChR PET tracer design and summarizes the binding properties and preclinical evaluation of recent mAChR tracer candidates. Furthermore, this work identifies the current major challenges in mAChR PET tracer development and provides a perspective on future developments in this area of research.
| S-EPMC8229778 | biostudies-literature
Project description:Acetylcholine is one of the most important endogenous neurotransmitters in a range of organisms spanning different animal phyla. Within pituitary gland it acts as autocrine and paracrine signal. In a current study we assessed expression profile of the different subunits of nicotinic as well as muscarinic acetylcholine receptors in RC-4BC cells, which are derived from rat pituitary gland tumor. Our findings indicate that β2, δ, and M2 subunits are expressed by the cells with the lowest Ct values compared to other tested subunits. The detected Ct values were 26.6±0.16, 27.95±0.5, and 28.8±0.25 for β2, δ, and M2 subunits, respectively.
| S-EPMC9757584 | biostudies-literature
Project description:The present study aimed to investigate the potential mechanisms used during signal transduction by M3 muscarinic acetylcholine receptor (CHRM3) in prostate cancer. The microarray datasets of GSE3325, including 5 clinically localized primary prostate cancers and 4 benign prostate tissues, were downloaded from the Gene Expression Omnibus database. The differentially-expressed genes (DEGs) in primary prostate cancer tissues compared with benign controls were screened using the Limma package. Gene Ontology and pathway enrichment analyses were performed using the Database for Annotation Visualization and Integrated Discovery. Next, a protein-protein interaction (PPI) network was constructed. Additionally, microRNAs (miRNAs) associated with DEGs were predicted and miRNA-target DEG analysis was performed using a Web-based Gene Set Analysis Toolkit. Finally, the PPI network and the miRNA-target DEG network were integrated using Cytoscape. In total, 224 DEGs were screened in the prostate cancer tissues, including 113 upregulated and 111 downregulated genes. CHRM3 and epidermal growth factor (EGF) were enriched in the regulation of the actin cytoskeleton. EGF and v-myc avian myelocytomatosis viral oncogene homolog (Myc) were enriched in the mitogen-activated protein kinase (MAPK) signaling pathway. EGF with the highest degree of connectivity was the hub node in the PPI network, and miR-34b could interact with Myc directly in the miRNA-target DEG network. EGF and Myc may exhibit significant roles in the progression of prostate cancer via regulation of the actin cytoskeleton and the MAPK signaling pathway. CHRM3 may activate these two pathways in prostate cancer progression. Thus, these two key factors and pathways may be crucial mechanisms during signal transduction by CHRM3 in prostate cancer.
| S-EPMC4727203 | biostudies-literature