Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Department of Physics, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Department of Chemical and Biological Engineering, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Mol Cell. 2019 Mar 7;73(5):971-984.e5. doi: 10.1016/j.molcel.2018.12.007. Epub 2019 Jan 17.
Both the timing and kinetics of neurotransmitter release depend on the positioning of clustered Ca channels in active zones to docked synaptic vesicles on presynaptic plasma membranes. However, how active zones form is not known. Here, we show that RIM and RIM-BP, via specific multivalent bindings, form dynamic and condensed assemblies through liquid-liquid phase separation. Voltage-gated Ca channels (VGCCs), via C-terminal-tail-mediated direct binding to both RIM and RIM-BP, can be enriched to the RIM and RIM-BP condensates. We further show that RIM and RIM-BP, together with VGCCs, form dense clusters on the supported lipid membrane bilayers via phase separation. Therefore, RIMs and RIM-BPs are plausible organizers of active zones, and the formation of RIM and RIM-BP condensates may cluster VGCCs into nano- or microdomains and position the clustered Ca channels with Ca sensors on docked vesicles for efficient and precise synaptic transmissions.
神经递质释放的时间和动力学取决于簇状 Ca 通道在突触前质膜上的活性区与停靠的突触小泡的定位。然而，活性区是如何形成的尚不清楚。在这里，我们表明，通过特定的多价结合，RIM 和 RIM-BP 形成动态且浓缩的组装体，通过液-液相分离。通过 C 末端尾部介导的对 RIM 和 RIM-BP 的直接结合，电压门控 Ca 通道 (VGCC) 可富集到 RIM 和 RIM-BP 凝聚物中。我们进一步表明，RIM 和 RIM-BP 与 VGCC 一起通过相分离在支持的脂质膜双层上形成致密簇。因此，RIM 和 RIM-BP 可能是活性区的组织者，RIM 和 RIM-BP 凝聚物的形成可能将 VGCC 簇集到纳米或微区，并将簇状 Ca 通道与停靠的囊泡上的 Ca 传感器定位，以实现高效和精确的突触传递。
