title: Schwann cells sense and control acetylcholine spillover at the neuromuscular junction by α7 nicotinic receptors and butyrylcholinesterase.
abstract: Terminal Schwann cells (TSCs) are key components of the mammalian neuromuscular junction (NMJ). How the TSCs sense the synaptic activity in physiological conditions remains unclear. We have taken advantage of the distinct localization of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) at the NMJ to bring out the function of different ACh receptors (AChRs). AChE is clustered by the collagen Q in the synaptic cleft and prevents the repetitive activation of muscle nicotinic AChRs. We found that BChE is anchored at the TSC by a proline-rich membrane anchor, the small transmembrane protein anchor of brain AChE. When BChE was specifically inhibited, ACh release was significant depressed through the activation of α7 nAChRs localized on the TSC and activated by the spillover of ACh. When both AChE and BChE were inhibited, the spillover increased and induced a dramatic reduction of ACh release that compromised the muscle twitch triggered by the nerve stimulation. α7 nAChRs at the TSC may act as a sensor for spillover of ACh adjusted by BChE and may represent an extrasynaptic sensor for homeostasis at the NMJ. In myasthenic rats, selective inhibition of AChE is more effective in rescuing muscle function than the simultaneous inhibition of AChE and BChE because the concomitant inhibition of BChE counteracts the positive action of AChE inhibition. These results show that inhibition of BChE should be avoided during the treatment of myasthenia and the pharmacological reversal of residual curarization after anesthesia.
authors.affiliation: COGNAC G, Université Paris Descartes, CNRS, Service de Santé des Armées, UMR 8257, MD 4, 75006 Paris, France, A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan 420088, Russia, Kazan Federal University, Kazan 420008, Russia.
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Petrov
authors.affiliation: COGNAC G, Université Paris Descartes, CNRS, Service de Santé des Armées, UMR 8257, MD 4, 75006 Paris, France, Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR 5239/ENS Lyon, Université de Lyon, 69364 Lyon cedex 07, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Girard
authors.affiliation: COGNAC G, Université Paris Descartes, CNRS, Service de Santé des Armées, UMR 8257, MD 4, 75006 Paris, France, Kazan Institute of Biochemistry and Biophysics, Kazan 420111, Russia, A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan 420088, Russia.
authors.forename: Alexandra D
authors.initials: AD
authors.lastname: Nikitashina
authors.affiliation: COGNAC G, Université Paris Descartes, CNRS, Service de Santé des Armées, UMR 8257, MD 4, 75006 Paris, France, Laboratory of Behavioral Physiology, Faculty of Medicine, University of Los Andes, Mérida 5101 Venezuela, and.
authors.forename: Cesare
authors.initials: C
authors.lastname: Colasante
authors.affiliation: Neuroscience Paris Seine, Université Pierre et Marie Curie UM CR 18, CNRS UMR 8246, INSERM U1130, 75005 Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bernard
authors.affiliation: Kazan Institute of Biochemistry and Biophysics, Kazan 420111, Russia, Kazan State Medical University, Kazan 420012, Russia.
authors.forename: Leniz
authors.initials: L
authors.lastname: Nurullin
authors.affiliation: COGNAC G, Université Paris Descartes, CNRS, Service de Santé des Armées, UMR 8257, MD 4, 75006 Paris, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Leroy
authors.affiliation: Kazan Institute of Biochemistry and Biophysics, Kazan 420111, Russia.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Samigullin
authors.affiliation: COGNAC G, Université Paris Descartes, CNRS, Service de Santé des Armées, UMR 8257, MD 4, 75006 Paris, France, Akdeniz University, Faculty of Engineering, 07058 Antalya, Turkey.
authors.forename: Omer
authors.initials: O
authors.lastname: Colak
authors.affiliation: Kazan Institute of Biochemistry and Biophysics, Kazan 420111, Russia, Kazan Federal University, Kazan 420008, Russia, Kazan State Medical University, Kazan 420012, Russia.
authors.forename: Evgenii
authors.initials: E
authors.lastname: Nikolsky
authors.affiliation: COGNAC G, Université Paris Descartes, CNRS, Service de Santé des Armées, UMR 8257, MD 4, 75006 Paris, France, Paris-Diderot University and Assistance Publique Hôpitaux de Paris, Department of Anesthesiology and Surgical Critical Care, Hôpital Saint-Louis, 75475 Paris cedex 10, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Plaud
authors.affiliation: COGNAC G, Université Paris Descartes, CNRS, Service de Santé des Armées, UMR 8257, MD 4, 75006 Paris, France, eric.krejci@parisdescartes.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Krejci
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000378:metabolism; D000549:Ambenonium Chloride / Q000494:pharmacology; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D005089:Exocytosis; D005260:Female; D008565:Membrane Proteins / Q000378:metabolism; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D051381:Rats; D012583:Schwann Cells / Q000378:metabolism* / Q000502:physiology; D013726:Terbutaline / Q000031:analogs & derivatives / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002038:Bungarotoxins; D002800:Cholinesterase Inhibitors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508016:PRiMA1 protein, rat; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000549:Ambenonium Chloride; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D013726:Terbutaline; D000109:Acetylcholine; C047766:bambuterol
keywords: acetylcholinesterase; glia; muscle; neuromuscular disease; synaptic homeostasis