Protein kinase C is a calcium sensor for presynaptic short-term plasticity.
Protein kinase C is a calcium sensor for presynaptic short-term plasticity.
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DOI：
10.7554/elife.03011
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发表时间：
2014-08-05
期刊：
影响因子：
7.7
通讯作者：
Regehr WG
中科院分区：
文献类型：
--
作者：
Fioravante D;Chu Y;de Jong AP;Leitges M;Kaeser PS;Regehr WG
在突触前终扣中，钙（Ca 2+）触发神经递质释放和短期突触可塑性。而synaptotagmins是已知的介导囊泡融合通过结合高的本地Ca 2+到他们的C2结构域，感测较小的全球Ca 2+的增加，以产生短期的可塑性的蛋白质仍然难以捉摸。在这里，我们确定了一个钙离子传感器强直后增强（PTP），一种形式的可塑性认为是短期记忆的基础。我们发现在Held突触功能成熟的萼中，Ca ~（2+）依赖的蛋白激酶C亚型α和β是PTP所必需的，而PKCαβ双敲除小鼠中PKCβ的表达可以挽救PTP。破坏与PKCβ C2结构域结合的Ca 2+特异性阻止PTP，而不损害其他PKCβ依赖性形式的突触增强。我们的结论是，不同的C2结构域的突触前蛋白参与不同的Ca 2+信号，并引起强直刺激引起的Ca 2+增加由PKCβ感应产生PTP。http://dx.doi.org/10.7554/eLife.03011.001大脑功能依赖于信息从一个脑细胞到下一个脑细胞的快速传递，这种传递在称为突触的连接处进行。当一个叫做动作电位的电信号在突触前细胞产生时，它会触发钙离子流入突触前细胞。这些离子激活特定的钙传感器，通过突触囊泡的胞吐作用触发突触前细胞释放称为神经递质的分子。这些神经递质与突触后细胞膜上的受体结合，并产生电信号，其大小是突触强度的量度。突触的强度会随着时间而改变，这种特性被称为可塑性。突触可以经历长期和短期的强度增加。强直后增强是一种持续数十秒的力量短期增加：它由突触前细胞中钙的增加触发，并涉及响应每个突触前动作电位而释放的神经递质量的增加。强直后增强被认为是短期记忆的基础。然而，检测强直后增强中钙积聚的传感器的身份尚不清楚。现在，Fioravante，Chu等人提供了第一个直接证据，证明一种称为蛋白激酶C的酶是负责的。转基因小鼠脑切片的电生理记录显示，缺乏蛋白激酶C的动物不显示强直后增强。然而，增强可以通过将酶重新引入突触前细胞来恢复。重要的是，缺乏结合钙能力的蛋白激酶C的突变形式不能触发强直后增强。蛋白激酶C代表了一类新的突触前钙传感器，支持短期可塑性。未来的研究很可能会发现这类传感器的其他成员，这些传感器允许不同的突触具有不同形式的短期可塑性。还需要进一步的研究来阐明短期可塑性的机制，并了解不同形式的短期可塑性如何与不同的功能和行为相关联。DOI：http://dx.doi.org/10.7554/eLife.03011.002网站
In presynaptic boutons, calcium (Ca2+) triggers both neurotransmitter release and short-term synaptic plasticity. Whereas synaptotagmins are known to mediate vesicle fusion through binding of high local Ca2+ to their C2 domains, the proteins that sense smaller global Ca2+ increases to produce short-term plasticity have remained elusive. Here, we identify a Ca2+ sensor for post-tetanic potentiation (PTP), a form of plasticity thought to underlie short-term memory. We find that at the functionally mature calyx of Held synapse the Ca2+-dependent protein kinase C isoforms α and β are necessary for PTP, and the expression of PKCβ in PKCαβ double knockout mice rescues PTP. Disruption of Ca2+ binding to the PKCβ C2 domain specifically prevents PTP without impairing other PKCβ-dependent forms of synaptic enhancement. We conclude that different C2-domain-containing presynaptic proteins are engaged by different Ca2+ signals, and that Ca2+ increases evoked by tetanic stimulation are sensed by PKCβ to produce PTP. DOI: http://dx.doi.org/10.7554/eLife.03011.001 Brain function is dependent upon the rapid transfer of information from one brain cell to the next at junctions known as synapses. When an electrical signal called an action potential is generated by the cell before the synapse, the presynaptic cell, it triggers an influx of calcium ions into that cell. These ions activate specific calcium sensors, triggering release of molecules called neurotransmitters from the presynaptic cell through exocytosis of synaptic vesicles. These neurotransmitters bind to receptors on the membrane of the postsynaptic cell, and produce an electrical signal whose size is a measure of synaptic strength. The strength of a synapse can change over time—a property that is called plasticity. Synapses can undergo both long-term and short-term increases in strength. Post-tetanic potentiation is a short-term increase in strength that lasts for tens of seconds: it is triggered by a calcium increase in the presynaptic cell and involves an increase in the amount of neurotransmitter released in response to each presynaptic action potential. Post-tetanic potentiation is thought to underlie short-term memory. However, the identity of the sensor that detects the build-up of calcium in post-tetanic potentiation was not known. Now, Fioravante, Chu et al. have provided the first direct evidence that an enzyme called protein kinase C is responsible. Electrophysiological recordings in brain slices from genetically modified mice revealed that animals that lack protein kinase C do not show post-tetanic potentiation. However, potentiation can be restored by re-introducing the enzyme into presynaptic cells. Importantly, a mutated version of protein kinase C that lacks the ability to bind calcium is unable to trigger post-tetanic potentiation. Protein kinase C represents a new class of presynaptic calcium sensors that supports short-term plasticity. It is likely that future studies will identify additional members of this class of sensors that allow different synapses to have different forms of short-term plasticity. Further research is also needed to clarify the mechanisms underlying short-term plasticity and to understand how different forms of short-term plasticity are associated with different functions and behaviors. DOI: http://dx.doi.org/10.7554/eLife.03011.002