title: The dystrophin-associated protein complex maintains muscle excitability by regulating Ca(2+)-dependent K(+) (BK) channel localization.
abstract: The dystrophin-associated protein complex (DAPC) consists of several transmembrane and intracellular scaffolding elements that have been implicated in maintaining the structure and morphology of the vertebrate neuromuscular junction (NMJ). Genetic linkage analysis has identified loss-of-function mutations in DAPC genes that give rise to degenerative muscular dystrophies. Although much is known about the involvement of the DAPC in maintaining muscle integrity, less is known about the precise contribution of the DAPC in cell signaling events. To better characterize the functional role of the DAPC at the NMJ, we used electrophysiology, immunohistochemistry, and fluorescent labeling to directly assess cholinergic synaptic transmission, ion channel localization, and muscle excitability in loss-of-function (lf) mutants of Caenorhabditis elegans DAPC homologues. We found that all DAPC mutants consistently display mislocalization of the Ca(2+)-gated K(+) channel, SLO-1, in muscle cells, while ionotropic acetylcholine receptor (AChR) expression and localization at the NMJ remained unaltered. Synaptic cholinergic signaling was also not significantly impacted across DAPC(lf) mutants. Consistent with these findings and the postsynaptic mislocalization of SLO-1, we observed an increase in muscle excitability downstream of cholinergic signaling. Based on our results, we conclude that the DAPC is not involved in regulating AChR architecture at the NMJ, but rather functions to control muscle excitability, in an activity-dependent manner, through the proper localization of SLO-1 channels.
authors.affiliation: Department of Biological Sciences, University of Illinois-Chicago, Chicago, Illinois 60607, USA.
authors.forename: Feyza
authors.initials: F
authors.lastname: Sancar
authors.forename: Denis
authors.initials: D
authors.lastname: Touroutine
authors.forename: Shangbang
authors.initials: S
authors.lastname: Gao
authors.forename: Hyun J
authors.initials: HJ
authors.lastname: Oh
authors.forename: Marie
authors.initials: M
authors.lastname: Gendrel
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Bessereau
authors.forename: Hongkyun
authors.initials: H
authors.lastname: Kim
authors.forename: Mei
authors.initials: M
authors.lastname: Zhen
authors.forename: Janet E
authors.initials: JE
authors.lastname: Richmond
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002794:Choline / Q000378:metabolism; D049028:Dystrophin-Associated Protein Complex / Q000235:genetics / Q000378:metabolism*; D017238:Genes, Helminth / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D032342:Muscle Cells / Q000378:metabolism; D009132:Muscles / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D021381:Protein Transport; D011950:Receptors, Cholinergic / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; D049028:Dystrophin-Associated Protein Complex; D051036:Large-Conductance Calcium-Activated Potassium Channels; D011950:Receptors, Cholinergic; C494845:slo-1 protein, C elegans; D049452:Green Fluorescent Proteins; D002794:Choline; D002118:Calcium