Prömer Jakob J, Wolske Sara, Castets Perrine, van Woerden Geeske M, Barresi Cinzia, O'Connor Kevin C, Herbst Ruth
Institute for Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Kinderspitalgasse 15, Vienna, 1090, Austria.
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, Geneva, CH-1211, Switzerland.
Sci Rep. 2025 Apr 28;15(1):14865. doi: 10.1038/s41598-025-95053-3.
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.
神经肌肉接头（NMJ）是下运动神经元与骨骼肌纤维之间独特的界面，对肌肉功能不可或缺。肌肉特异性激酶（MuSK）维持着其在每根肌纤维中心局部形成的严格控制以及终生的维持。MuSK作为突触后乙酰胆碱受体聚集的中心调节因子。MuSK的局部和时间控制信号主要通过酪氨酸自身磷酸化及其抑制来实现。先前的研究表明，激活域的丝氨酸磷酸化是MuSK激活的另一种调节因子。在这里，我们确定钙/钙调蛋白依赖性蛋白激酶II（CaMK2），特别是CaMK2β是MuSK激活的新型催化剂，并证实了其在异源细胞中磷酸化MuSK的能力。然而，虽然肌肉细胞中缺乏CaMK2β会减少乙酰胆碱受体聚集，但MuSK磷酸化没有变化。因此，我们排除了MuSK磷酸化是1型强直性肌营养不良小鼠模型中突触断裂的原因（该模型中缺少CaMK2β的肌肉特异性剪接变体），也排除了其是CaMK2β基因敲除动物共济失调或肌肉发育延迟的原因。对CaMK2β基因敲除小鼠肌肉的组织学特征分析表明，CaMK2β在快速糖酵解型肌肉与慢速氧化型肌肉中具有特定作用。综上所述，我们的数据表明MuSK可被CaMK2β磷酸化，但在神经肌肉接头处，CaMK2β的缺失可能由其他CaMK2旁系同源物代偿。
