MuSK is a substrate for CaMK2β but this interaction is dispensable for MuSK activation in vivo
Abstract The neuromuscular junction (NMJ) is the unique interface between lower motor neurons and skeletal muscle fibers and is indispensable for muscle function. Tight control of its localized formation at the center of every muscle fiber, and maintenance throughout lifetime are sustained by muscle...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-95053-3 |
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| Summary: | Abstract The neuromuscular junction (NMJ) is the unique interface between lower motor neurons and skeletal muscle fibers and is indispensable for muscle function. Tight control of its localized formation at the center of every muscle fiber, and maintenance throughout lifetime are sustained by muscle-specific kinase (MuSK). MuSK acts as central regulator of acetylcholine receptor clustering at the postsynapse. Localized and temporally controlled signaling of MuSK is primarily achieved by tyrosine autophosphorylation and inhibition thereof. Previous investigations suggested serine phosphorylation of the activation domain as an additional modulator of MuSK activation. Here we identified calcium/calmodulin dependent protein kinase II (CaMK2) and in particular CaMK2β as novel catalyst of MuSK activation and confirmed its capability to phosphorylate MuSK in heterologous cells. However, whereas CaMK2β absence in muscle cells reduced AChR clustering, MuSK phosphorylation was unchanged. Accordingly, we ruled out MuSK phosphorylation as the cause of synapse fragmentation in a mouse model for myotonic dystrophy type 1, in which the muscle-specific splice-variant of CaMK2β is missing, or as the cause of ataxia or delayed muscle development in CaMK2β knockout animals. Histological characterization of muscles of CaMK2β knockout mice indicated specific roles of CaMK2β in fast glycolytic versus slow oxidative muscle. Taken together, our data shows that MuSK can be phosphorylated by CaMK2β, but loss of CaMK2β is likely compensated by other CaMK2 paralogs at the NMJ. |
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| ISSN: | 2045-2322 |