Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2031-6. doi: 10.1073/pnas.0914087107. Epub 2010 Jan 19.
Myosin V motor proteins facilitate recycling of synaptic receptors, including AMPA and acetylcholine receptors, in central and peripheral synapses, respectively. To shed light on the regulation of receptor recycling, we employed in vivo imaging of mouse neuromuscular synapses. We found that myosin Va cooperates with PKA on the postsynapse to maintain size and integrity of the synapse; this cooperation also regulated the lifetime of acetylcholine receptors. Myosin Va and PKA colocalized in subsynaptic enrichments. These accumulations were crucial for synaptic integrity and proper cAMP signaling, and were dependent on AKAP function, myosin Va, and an intact actin cytoskeleton. The neuropeptide and cAMP agonist, calcitonin-gene related peptide, rescued fragmentation of synapses upon denervation. We hypothesize that neuronal ligands trigger local activation of PKA, which in turn controls synaptic integrity and turnover of receptors. To this end, myosin Va mediates correct positioning of PKA in a postsynaptic microdomain, presumably by tethering PKA to the actin cytoskeleton.
肌球蛋白 Va 分子马达蛋白促进中枢和外周突触中 AMPA 和乙酰胆碱受体等突触受体的循环回收。为了阐明受体循环回收的调控机制，我们采用活体成像技术研究了小鼠神经肌肉突触。我们发现肌球蛋白 Va 与突触后 PKA 合作维持突触的大小和完整性；这种合作还调节乙酰胆碱受体的寿命。肌球蛋白 Va 和 PKA 在突触下富集区共定位。这些聚集对于突触完整性和适当的 cAMP 信号转导至关重要，并且依赖于 AKAP 功能、肌球蛋白 Va 和完整的肌动蛋白细胞骨架。神经肽和 cAMP 激动剂降钙素基因相关肽可挽救去神经后突触的碎片化。我们假设神经元配体触发 PKA 的局部激活，反过来又控制突触的完整性和受体的周转率。为此，肌球蛋白 Va 通过将 PKA 固定在肌动蛋白细胞骨架上，介导 PKA 在突触后微域中的正确定位。
