The Dystrophin-associated Protein Complex Maintains Muscle Excitability by Regulating Ca2+-dependent K+ (BK) Channel Localization

• Published in: The Journal of biological chemistry Vol. 286; no. 38; pp. 33501 - 33510
• Main Authors: Sancar, Feyza, Touroutine, Denis, Gao, Shangbang, Oh, Hyun J., Gendrel, Marie, Bessereau, Jean-Louis, Kim, Hongkyun, Zhen, Mei, Richmond, Janet E.
• Format: Journal Article
• Language: English
• Published: 9650 Rockville Pike, Bethesda, MD 20814, U.S.A Elsevier Inc 23.09.2011; American Society for Biochemistry and Molecular Biology
• Subjects: C. elegans; Calcium-gated Potassium Channel; Electrophysiology; Membrane Biophysics; Molecular Biophysics; Muscle Excitability; Muscular Dystrophy; Neuromuscular Junction; Potassium Channels; Skeletal Muscle; Potassium Channels; C. elegans; Skeletal Muscle; Muscle Excitability; Neuromuscular Junction; Membrane Biophysics; Electrophysiology; Muscular Dystrophy; Calcium-gated Potassium Channel
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.227678

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 Ca2+-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.