Synaptic activity regulates AMPA receptor trafficking through different recycling pathways.
Synaptic activity regulates AMPA receptor trafficking through different recycling pathways.
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DOI：
10.7554/elife.06878
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发表时间：
2015-05-13
期刊：
影响因子：
7.7
通讯作者：
Green WN
中科院分区：
文献类型：
--
作者：
Zheng N;Jeyifous O;Munro C;Montgomery JM;Green WN
脑内谷氨酸能突触强度的变化依赖于AMPA型谷氨酸受体(AMPAR)的循环，这种循环被认为是通过单一的局部途径发生的。在这项研究中，我们提出了AMPAR循环通过突触活动调节的不同途径发生的证据。在没有突触刺激的情况下，大多数AMPAR在含有GTPase Arf6的动力非依赖性内体中循环。在转铁蛋白受体(TFR)标记的动力蛋白依赖的内体中，很少有AMPAR被回收。Ampar循环被GTPase TC10的改变所阻止，TC10与Arf6内切体共定位。减少AMPAR循环的TC10突变体对长期增强(LTP)的AMPAR水平升高没有影响，对长期抑制的AMPAR水平下降几乎没有影响。然而，在LTP后，含有TFR的循环内体中内化的AMPAR水平增加，表明AMPAR循环通过具有突触可塑性的动力蛋白依赖的途径增加。LTP诱导的AMPAR内吞作用与当地循环作为增加表面受体的来源不一致，这表明AMPAR是从其他位置贩运来的。DOI：http://dx.doi.org/10.7554/eLife.06878.001细胞称为神经元，以电信号的形式在大脑周围传递信息。在两个神经元之间的交界处--称为突触--一个电信号触发被称为神经递质的小分子的释放。这些分子穿过两个神经元之间的缝隙，在第二个神经元中触发新的电信号。记忆可以储存在突触中：高水平的活动可以“加强”突触，从而增加神经元之间的信息传输。在许多突触中，一种名为谷氨酸的分子是神经递质。在神经元表面发现的名为AMPAR的蛋白质可以检测谷氨酸，并沿着第二个神经元传递信号。突触的强度由AMPAR水平的变化控制，通过“循环”，AMPAR蛋白从突触中移除，内化，然后返回突触。据认为，AMPAR只通过突触的一条途径进行循环。然而，当突触活跃时，回收的数量要高得多，目前还不清楚这是如何工作的。现在，郑等人。在显微镜下使用荧光标签跟踪大鼠突触中AMPAR的循环。实验表明，当突触不活跃时，大多数AMPAR通过一种名为Arf6的蛋白质标记的途径进行循环。然而，当突触活跃时，大多数AMPAR通过一条不同的途径循环，这些途径以所谓的转铁蛋白受体蛋白为标志。实验还显示，一种名为TC10的蛋白质与Arf6一起参与了AMPAR的再循环，但当突触活跃和加强时，再循环并不需要TC10。出乎意料的是，AMPAR的内化--通过涉及转铁蛋白受体的过程--在突触加强过程中增加。这表明，一些额外的AMPAR蛋白被送到膜上，来自神经元的其他部分，而不是突触。郑等人。S的发现提供了证据，证明根据突触的活性，AMPAR通过不同的途径被循环。下一个挑战将是直接测试AMPAR是否从神经元的其他部分运输到强化的突触，并了解这是如何工作的。DOI：http://dx.doi.org/10.7554/eLife.06878.002
Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. In this study, we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites. DOI: http://dx.doi.org/10.7554/eLife.06878.001 Cells called neurons transmit information around the brain in the form of electrical signals. At a junction between two neurons—called a synapse—an electrical signal triggers the release of small molecules called neurotransmitters. These molecules travel across the gap between the two neurons and trigger a new electrical signal in the second neuron. Memories can be stored in synapses: high levels of activity can ‘strengthen’ the synapse, which increases the transfer of information between the neurons. In many synapses, a molecule called glutamate is the neurotransmitter. Proteins called AMPARs, which are found on the surface of the neuron, can detect glutamate and transmit the signal along the second neuron. The strength of synapses is controlled by changes in AMPAR levels through ‘recycling’, where AMPAR proteins are removed from synapses, internalized and later returned to synapses. It was thought that AMPARs are recycled via just one pathway at synapses. However, the amount of recycling is much higher when the synapses are active and it is not clear how this works. Now, Zheng et al. have used fluorescent tags to track the recycling of AMPARs in synapses from rats under a microscope. The experiments show that when the synapses are not active, most AMPARs are recycled via a pathway marked by a protein called Arf6. However, when the synapses are active, most AMPAR is recycled via a different route marked by so-called ‘transferrin receptor’ proteins. The experiments also reveal that a protein called TC10 is involved in recycling AMPARs alongside Arf6, but is not required for recycling when the synapses are active and being strengthened. Unexpectedly, AMPAR internalization—via the process involving transferrin receptors—increases during synapse strengthening. This suggests that some of the extra AMPAR proteins sent to the membrane have come from other parts of the neuron away from the synapse. Zheng et al.'s findings provide evidence that AMPARs are recycled through different routes depending on the activity of the synapse. The next challenge will be to directly test whether AMPARs are transported from other parts of the neuron to the strengthened synapse and to understand how this works. DOI: http://dx.doi.org/10.7554/eLife.06878.002