Bromann P A, Zhou H, Sanes J R
Department of Anatomy and Neurobiology, Washington University Medical School, 660 South Euclid, St. Louis, MO 63110, USA.
Neuroscience. 2004;125(2):417-26. doi: 10.1016/j.neuroscience.2003.12.031.
The muscle-specific receptor tyrosine kinase (MuSK) is co-localized with nicotinic acetylcholine receptors (AChRs) in the postsynaptic membrane of the skeletal neuromuscular junction, and is required for all known aspects of postsynaptic differentiation. Studies in vitro have shown that Z(+)-agrin, a nerve-derived proteoglycan, activates MuSK's kinase activity to promote clustering of AChRs and MuSK itself with a cytoplasmic, receptor-associated protein, rapsyn. These studies, however, have used soluble forms of agrin, whereas agrin is cell- or matrix-attached in vivo. We show here that immobilized (particle- or cell-attached) agrin but not soluble agrin is able to aggregate MuSK in the absence of rapsyn and that this aggregation does not require MuSK's kinase activity but does require MuSK's cytoplasmic domain. Moreover, immobilized agrin can promote clustering of AChRs by a mechanism that requires MuSK and rapsyn but does not require MuSK's kinase activity. These results imply that rapsyn and signaling components activated by MuSK kinase may be dispensable for some early aspects of postsynaptic differentiation.
肌肉特异性受体酪氨酸激酶（MuSK）与烟碱型乙酰胆碱受体（AChRs）共定位于骨骼肌神经肌肉接头的突触后膜，并且是突触后分化所有已知方面所必需的。体外研究表明，神经源性蛋白聚糖Z（+）-聚集蛋白聚糖可激活MuSK的激酶活性，以促进AChRs和MuSK自身与一种细胞质、受体相关蛋白rapsyn聚集在一起。然而，这些研究使用的是聚集蛋白聚糖的可溶性形式，而聚集蛋白聚糖在体内是与细胞或基质结合的。我们在此表明，固定化（颗粒或细胞附着）的聚集蛋白聚糖而非可溶性聚集蛋白聚糖能够在没有rapsyn的情况下聚集MuSK，并且这种聚集不需要MuSK的激酶活性，但确实需要MuSK的细胞质结构域。此外，固定化的聚集蛋白聚糖可通过一种需要MuSK和rapsyn但不需要MuSK激酶活性的机制促进AChRs的聚集。这些结果表明，rapsyn和由MuSK激酶激活的信号成分对于突触后分化的某些早期方面可能是不必要的。
