Nicotinic Acetylcholine Receptor Stability at the NMJ Deficient in alpha-Syntrophin In Vivo

作者：Martinez Pena y Valenzuela Isabel; Mouslim Chakib; Pires Oliveira Marcelo; Adams Marvin E; Froehner Stanley C; Akaaboune Mohammed^*

来源：Journal of Neuroscience, 2011, 31(43): 15586-15596.

DOI：10.1523/JNEUROSCI.4038-11.2011

alpha-Syntrophin (alpha-syn), a scaffold protein, links signaling molecules to the dystrophin-glycoprotein complex. Absence of alpha-syn from the DGC is known to lead to structurally aberrant neuromuscular junctions (NMJs) with few acetylcholine receptors (AChRs) clustered at synaptic sites. Using alpha-syn knock-out mice, we show that during the first postnatal week, alpha-syn is not required for synapse formation. However, at postnatal day 6 (P6)-P7, the structural integrity of the postsynaptic apparatus is altered, the turnover rate of AChRs increases significantly, and the number/density of AChRs is impaired. At the adult alpha-syn(-/-) NMJ, the turnover rate of AChRs is similar to 4 times faster than wild-type synapses, and most removed receptors are targeted to degradation as few AChRs recycled to synaptic sites. Biochemical analyses show that in muscle cells of adult knock-out alpha-syn mice, total AChRs and scaffold protein rapsyn are significantly reduced, the 89 kDa and 75 kDa isoforms of tyrosine phosphorylated alpha-dystrobrevin (alpha-dbn) 1 (which are required for the maintenance and stability of AChR in alpha-dbn(-/-) synapses) are barely detectable. Electroporation of GFP-alpha-dbn1 in alpha-syn(-/-) muscle cells partially restored receptor density, turnover rate, and the structural integrity of the postsynaptic apparatus, whereas expression of rapsyn-GFP failed to rescue the alpha-syn(-/-) synaptic phenotype. These results demonstrate that alpha-syn is required for the maturation and stability of the postsynaptic apparatus and suggest that alpha-syn may act via alpha-dbn1.

• 出版日期2011-10-26