Han Yunyun, Kaeser Pascal S, Südhof Thomas C, Schneggenburger Ralf
Laboratory of Synaptic Mechanisms, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Neuron. 2011 Jan 27;69(2):304-16. doi: 10.1016/j.neuron.2010.12.014.
At presynaptic active zones, neurotransmitter release is initiated by the opening of voltage-gated Ca²+ channels close to docked vesicles. The mechanisms that enrich Ca²+ channels at active zones are, however, largely unknown, possibly because of the limited presynaptic accessibility of most synapses. Here, we have established a Cre-lox based conditional knockout approach at a presynaptically accessible central nervous system synapse, the calyx of Held, to directly study the functions of RIM proteins. Removal of all RIM1/2 isoforms strongly reduced the presynaptic Ca²+ channel density, revealing a role of RIM proteins in Ca²+ channel targeting. Removal of RIMs also reduced the readily releasable pool, paralleled by a similar reduction of the number of docked vesicles, and the Ca²+ channel-vesicle coupling was decreased. Thus, RIM proteins co-ordinately regulate key functions for fast transmitter release, enabling a high presynaptic Ca²+ channel density and vesicle docking at the active zone.
在突触前活动区，神经递质的释放是由靠近停靠囊泡的电压门控Ca²⁺通道开放引发的。然而，在活动区富集Ca²⁺通道的机制在很大程度上尚不清楚，这可能是因为大多数突触的突触前可及性有限。在这里，我们在一个突触前可及的中枢神经系统突触——前庭神经终器，建立了一种基于Cre-lox的条件性敲除方法，以直接研究RIM蛋白的功能。去除所有RIM1/2亚型会强烈降低突触前Ca²⁺通道密度，揭示了RIM蛋白在Ca²⁺通道靶向中的作用。去除RIMs还会减少易释放池，同时停靠囊泡数量也有类似减少，并且Ca²⁺通道-囊泡偶联减少。因此，RIM蛋白协同调节快速递质释放的关键功能，使突触前Ca²⁺通道密度高且囊泡能停靠在活动区。
