Kaeser Pascal S, Kwon Hyung-Bae, Chiu Chiayu Q, Deng Lunbin, Castillo Pablo E, Südhof Thomas C
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA.
J Neurosci. 2008 Dec 10;28(50):13435-47. doi: 10.1523/JNEUROSCI.3235-08.2008.
At a synapse, presynaptic terminals form a specialized area of the plasma membrane called the active zone that mediates neurotransmitter release. RIM1alpha is a multidomain protein that constitutes a central component of the active zone by binding to other active zone proteins such as Munc13 s, alpha-liprins, and ELKS, and to synaptic vesicle proteins such as Rab3 and synaptotagmin-1. In mice, knockout of RIM1alpha significantly impairs synaptic vesicle priming and presynaptic long-term plasticity, but is not lethal. We now find that the RIM1 gene encodes a second, previously unknown RIM1 isoform called RIM1beta that is upregulated in RIM1alpha knock-out mice. RIM1beta is identical to RIM1alpha except for the N terminus where RIM1beta lacks the N-terminal Rab3-binding sequence of RIM1alpha. Using newly generated knock-out mice lacking both RIM1alpha and RIM1beta, we demonstrate that different from the deletion of only RIM1alpha, deletion of both RIM1alpha and RIM1beta severely impairs mouse survival. Electrophysiological analyses show that the RIM1alphabeta deletion abolishes long-term presynaptic plasticity, as does RIM1alpha deletion alone. In contrast, the impairment in synaptic strength and short-term synaptic plasticity that is caused by the RIM1alpha deletion is aggravated by the deletion of both RIM1alpha and RIM1beta. Thus, our data indicate that the RIM1 gene encodes two different isoforms that perform overlapping but distinct functions in neurotransmitter release.
在突触处，突触前终末形成质膜的一个特化区域，称为活性区，它介导神经递质的释放。RIM1α是一种多结构域蛋白，通过与其他活性区蛋白（如Munc13、α-脂蛋白和ELKS）以及突触小泡蛋白（如Rab3和突触结合蛋白-1）结合，构成活性区的核心成分。在小鼠中，RIM1α基因敲除显著损害突触小泡的启动和突触前长期可塑性，但不会导致死亡。我们现在发现，RIM1基因编码第二种以前未知的RIM1亚型，称为RIM1β，它在RIM1α基因敲除小鼠中上调。RIM1β与RIM1α相同，只是在N端，RIM1β缺少RIM1α的N端Rab3结合序列。利用新生成的同时缺乏RIM1α和RIM1β的基因敲除小鼠，我们证明，与仅缺失RIM1α不同，同时缺失RIM1α和RIM1β会严重损害小鼠的生存能力。电生理分析表明，RIM1αβ缺失消除了突触前长期可塑性，单独缺失RIM1α时也是如此。相反，RIM1α缺失引起的突触强度和短期突触可塑性损伤，在同时缺失RIM1α和RIM1β时会加剧。因此，我们的数据表明，RIM1基因编码两种不同的亚型，它们在神经递质释放中发挥重叠但不同的功能。
