title: Neuregulin 1-ErbB module in C-bouton synapses on somatic motor neurons: molecular compartmentation and response to peripheral nerve injury.
abstract: The electric activity of lower motor neurons (MNs) appears to play a role in determining cell-vulnerability in MN diseases. MN excitability is modulated by cholinergic inputs through C-type synaptic boutons, which display an endoplasmic reticulum-related subsurface cistern (SSC) adjacent to the postsynaptic membrane. Besides cholinergic molecules, a constellation of proteins involved in different signal-transduction pathways are clustered at C-type synaptic sites (M2 muscarinic receptors, Kv2.1 potassium channels, Ca2+activated K+[SK] channels, and sigma-1 receptors [S1R]), but their collective functional significance so far remains unknown. We have previously suggested that neuregulin-1 (NRG1)/ErbBs-based retrograde signalling occurs at this synapse. To better understand signalling through C-boutons, we performed an analysis of the distribution of C-bouton-associated signalling proteins. We show that within SSC, S1R, Kv2.1 and NRG1 are clustered in highly specific, non-overlapping, microdomains, whereas ErbB2 and ErbB4 are present in the adjacent presynaptic compartment. This organization may define highly ordered and spatially restricted sites for different signal-transduction pathways. SSC associated proteins are disrupted in axotomised MNs together with the activation of microglia, which display a positive chemotactism to C-bouton sites. This indicates that C-bouton associated molecules are also involved in neuroinflammatory signalling in diseased MNs, emerging as new potential therapeutic targets.
authors.affiliation: Departament de Medicina Experimental, Patologia Neuromuscular Experimental, Facultat de Medicina, Universitat de Lleida/IRBLLEIDA, Av. Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Casanovas
authors.affiliation: Departament de Medicina Experimental, Patologia Neuromuscular Experimental, Facultat de Medicina, Universitat de Lleida/IRBLLEIDA, Av. Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Salvany
authors.affiliation: Departament de Medicina Experimental, Patologia Neuromuscular Experimental, Facultat de Medicina, Universitat de Lleida/IRBLLEIDA, Av. Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Lahoz
authors.affiliation: Departament de Medicina Experimental, Patologia Neuromuscular Experimental, Facultat de Medicina, Universitat de Lleida/IRBLLEIDA, Av. Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Tarabal
authors.affiliation: Departament de Medicina Experimental, Patologia Neuromuscular Experimental, Facultat de Medicina, Universitat de Lleida/IRBLLEIDA, Av. Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
authors.forename: Lídia
authors.initials: L
authors.lastname: Piedrafita
authors.affiliation: Departament de Medicina Experimental, Patologia Neuromuscular Experimental, Facultat de Medicina, Universitat de Lleida/IRBLLEIDA, Av. Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
authors.forename: Raimundo
authors.initials: R
authors.lastname: Sabater
authors.affiliation: Departament de Medicina Experimental, Patologia Neuromuscular Experimental, Facultat de Medicina, Universitat de Lleida/IRBLLEIDA, Av. Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Hernández
authors.affiliation: Departament de Medicina Experimental, Patologia Neuromuscular Experimental, Facultat de Medicina, Universitat de Lleida/IRBLLEIDA, Av. Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Calderó
authors.affiliation: Departament de Medicina Experimental, Patologia Neuromuscular Experimental, Facultat de Medicina, Universitat de Lleida/IRBLLEIDA, Av. Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
authors.forename: Josep E
authors.initials: JE
authors.lastname: Esquerda
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism* / Q000648:ultrastructure; D020890:Neuregulin-1 / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D066247:Receptor, ErbB-4 / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism; D051669:Shab Potassium Channels / Q000378:metabolism; D015398:Signal Transduction; D000097605:Sigma-1 Receptor
chemical_list: D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D017480:Receptors, sigma; D051669:Shab Potassium Channels; D000097605:Sigma-1 Receptor; C496990:Kcnb1 protein, mouse; C490581:Nrg1 protein, mouse; C524056:Erbb2 protein, mouse