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      Non-Neuronal Functions of the M 2 Muscarinic Acetylcholine Receptor

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          Abstract

          Acetylcholine is an important neurotransmitter whose effects are mediated by two classes of receptors. The nicotinic acetylcholine receptors are ion channels, whereas the muscarinic receptors belong to the large family of G protein coupled seven transmembrane helix receptors. Beyond its function in neuronal systems, it has become evident that acetylcholine also plays an important role in non-neuronal cells such as epithelial and immune cells. Furthermore, many cell types in the periphery are capable of synthesizing acetylcholine and express at least some of the receptors. In this review, we summarize the non-neuronal functions of the muscarinic acetylcholine receptors, especially those of the M 2 muscarinic receptor in epithelial cells. We will review the mechanisms of signaling by the M 2 receptor but also the cellular trafficking and ARF6 mediated endocytosis of this receptor, which play an important role in the regulation of signaling events. In addition, we provide an overview of the M 2 receptor in human pathological conditions such as autoimmune diseases and cancer.

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          Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans.

          I Wessler, C Kirkpatrick (2008)
          Animal life is controlled by neurons and in this setting cholinergic neurons play an important role. Cholinergic neurons release ACh, which via nicotinic and muscarinic receptors (n- and mAChRs) mediate chemical neurotransmission, a highly integrative process. Thus, the organism responds to external and internal stimuli to maintain and optimize survival and mood. Blockade of cholinergic neurotransmission is followed by immediate death. However, cholinergic communication has been established from the beginning of life in primitive organisms such as bacteria, algae, protozoa, sponge and primitive plants and fungi, irrespective of neurons. Tubocurarine- and atropine-sensitive effects are observed in plants indicating functional significance. All components of the cholinergic system (ChAT, ACh, n- and mAChRs, high-affinity choline uptake, esterase) have been demonstrated in mammalian non-neuronal cells, including those of humans. Embryonic stem cells (mice), epithelial, endothelial and immune cells synthesize ACh, which via differently expressed patterns of n- and mAChRs modulates cell activities to respond to internal or external stimuli. This helps to maintain and optimize cell function, such as proliferation, differentiation, formation of a physical barrier, migration, and ion and water movements. Blockade of n- and mACHRs on non-innervated cells causes cellular dysfunction and/or cell death. Thus, cholinergic signalling in non-neuronal cells is comparable to cholinergic neurotransmission. Dysfunction of the non-neuronal cholinergic system is involved in the pathogenesis of diseases. Alterations have been detected in inflammatory processes and a pathobiologic role of non-neuronal ACh in different diseases is discussed. The present article reviews recent findings about the non-neuronal cholinergic system in humans.
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            EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF.

            N Prenzel, E B Zwick, H Daub … (2000)
            Cross-communication between different signalling systems allows the integration of the great diversity of stimuli that a cell receives under varying physiological situations. The transactivation of epidermal growth factor receptor (EGFR)-dependent signalling pathways upon stimulation of G-protein-coupled receptors (GPCRs), which are critical for the mitogenic activity of ligands such as lysophosphatidic acid, endothelin, thrombin, bombesin and carbachol, provides evidence for such an interconnected communication network. Here we show that EGFR transactivation upon GPCR stimulation involves proHB-EGF and a metalloproteinase activity that is rapidly induced upon GPCR-ligand interaction. We show that inhibition of proHB-EGF processing blocks GPCR-induced EGFR transactivation and downstream signals. The pathophysiological significance of this mechanism is demonstrated by inhibition of constitutive EGFR activity upon treatment of PC3 prostate carcinoma cells with the metalloproteinase inhibitor batimastat. Together, our results establish a new mechanistic concept for cross-communication among different signalling systems.
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              Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist

              Kazuko Haga, Andrew C. Kruse, Hidetsugu Asada … (2012)
              The parasympathetic limb of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G protein coupled receptors (GPCRs) that mediate the response to acetylcholine released from parasympathetic nerves. 1–5 Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiologic control of cardiovascular function through activation of G protein-coupled inwardly-rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of antagonist-bound M2 receptor, the first human acetylcholine receptor to be characterized structurally. The antagonist QNB binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all 5 muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The M2 receptor structure provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genes (Basel)
                Journal ID (iso-abbrev): Genes (Basel)
                Journal ID (publisher-id): genes
                Title: Genes
                Publisher: MDPI
                ISSN (Electronic): 2073-4425
                Publication date (Electronic): 02 April 2013
                Publication date Collection: June 2013
                Volume: 4
                Issue: 2
                Pages: 171-197
                Affiliations
                Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany; E-Mails: Wymke.Ockenga@ 123456biochemie.med.uni-giessen.de (W.O.); Sina.Kuehne@ 123456biochemie.med.uni-giessen.de (S.K.); Simonebocksberger@ 123456web.de (S.B.); Antje.Banning@ 123456biochemie.med.uni-giessen.de (A.B.)
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: Ritva.Tikkanen@ 123456biochemie.med.uni-giessen.de ; Tel.: +49-641-9947-420; Fax: +49-641-9947-429.
                Article
                Publisher ID: genes-04-00171
                DOI: 10.3390/genes4020171
                PMC ID: 3899973
                PubMed ID: 24705159
                SO-VID: 99d08123-6197-41c4-9c03-7bae7b27819f
                Copyright © © 2013 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 31 January 2013
                Date revision received : 10 March 2013
                Date accepted : 25 March 2013
                Categories
                Subject: Review

                Keywords: acetylcholine,g proteins,signal transduction,muscarinic receptors
                Data availability:
                Keywords: acetylcholine, g proteins, signal transduction, muscarinic receptors

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