Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University of Hamburg Medical School, Falkenried 94, D-20251 Hamburg, Germany.
Neuron. 2011 Apr 14;70(1):66-81. doi: 10.1016/j.neuron.2011.03.008.
Intracellular transport regulates protein turnover including endocytosis. Because of the spatial segregation of F-actin and microtubules, internalized cargo vesicles need to employ myosin and dynein motors to traverse both cytoskeletal compartments. Factors specifying cargo delivery across both tracks remain unknown. We identified muskelin to interconnect retrograde F-actin- and microtubule-dependent GABA(A) receptor (GABA(A)R) trafficking. GABA(A)Rs regulate synaptic transmission, plasticity, and network oscillations. GABA(A)R α1 and muskelin interact directly, undergo neuronal cotransport, and associate with myosin VI or dynein motor complexes in subsequent steps of GABA(A)R endocytosis. Inhibition of either transport route selectively interferes with receptor internalization or degradation. Newly generated muskelin KO mice display depletion of both transport steps and a high-frequency ripple oscillation phenotype. A diluted coat color of muskelin KOs further suggests muskelin transport functions beyond neurons. Our data suggest the concept that specific trafficking factors help cargoes to traverse both F-actin and microtubule compartments, thereby regulating their fate.
细胞内运输调节蛋白质周转，包括内吞作用。由于 F-肌动蛋白和微管的空间隔离，内化的货物囊泡需要肌球蛋白和动力蛋白马达来穿越这两个细胞骨架隔间。指定货物在两条轨道上传递的因素尚不清楚。我们发现肌联蛋白将逆行 F-肌动蛋白和微管依赖性 GABA(A)受体 (GABA(A)R) 运输联系在一起。GABA(A)R 调节突触传递、可塑性和网络振荡。GABA(A)R α1 和肌联蛋白直接相互作用，进行神经元共运输，并在 GABA(A)R 内吞作用的后续步骤中与肌球蛋白 VI 或动力蛋白马达复合物相关联。两种运输途径的抑制都选择性地干扰了受体的内化或降解。新生成的肌联蛋白 KO 小鼠显示两种运输步骤的耗竭以及高频波纹振荡表型。肌联蛋白 KO 的稀释毛色进一步表明肌联蛋白的运输功能超出了神经元。我们的数据表明，特定的运输因子有助于货物穿越 F-肌动蛋白和微管隔间，从而调节它们的命运。
