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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Rim1α Phosphorylation At Serine-413 By Protein Kinase A Is Not Required For Presynaptic Long-term Plasticity Or Learning
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Rim1α Phosphorylation At Serine-413 By Protein Kinase A Is Not Required For Presynaptic Long-term Plasticity Or Learning

机译：突触前长期可塑性或学习不需要蛋白激酶A在丝氨酸413处的Rim1α磷酸化

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摘要

Activation of presynaptic cAMP-dependent protein kinase A (PKA) triggers presynaptic long-term plasticity in synapses such as cere-bellar parallel fiber and hippocampal mossy fiber synapses. RIM1α, a large multidomain protein that forms a scaffold at the presynaptic active zone, is essential for presynaptic long-term plasticity in these synapses and is phosphorylated by PKA at serine-413. Previous studies suggested that phosphorylation of RIM1α at serine-413 is required for presynaptic long-term potentiation in parallel fiber synapses formed in vitro by cultured cerebellar neurons and that this type of presynaptic long-term potentiation is mediated by binding of 14-3-3 proteins to phosphorylated serine-413. To test the role of serine-413 phosphorylation in vivo, we have now produced knockin mice in which serine-413 is mutated to alanine. Surprisingly, we find that in these mutant mice, three different forms of presynaptic PKA-dependent long-term plasticity are normal. Furthermore, we observed that in contrast to RIM1α KO mice, RIM1 knockin mice containing the serine-413 substitution exhibit normal learning capabilities. The lack of an effect of the serine-413 mutation of RIM1α is not due to compensation by RIM2α because mice carrying both the serine-413 substitution and a RIM2α deletion still exhibited normal long-term presynaptic plasticity. Thus, phosphorylation of serine-413 of RIM1α is not essential for PKA-dependent long-term presynaptic plasticity in vivo, suggesting that PKA operates by a different mechanism despite the dependence of long-term presynaptic plasticity on RIM1α.
机译：突触前依赖cAMP的蛋白激酶A（PKA）的激活会触发突触前长期可塑性，例如小脑-平行纤维突触和海马苔藓纤维突触。 RIM1α是在突触前活性区形成支架的大型多结构域蛋白，对于这些突触中的突触前长期可塑性是必不可少的，并由PKA丝氨酸413磷酸化。先前的研究表明，在培养的小脑神经元体外形成的平行纤维突触中，突触前的长期增强需要在丝氨酸413处使RIM1α磷酸化，而这种突触前的长期增强是由14-3-3的结合介导的蛋白磷酸化丝氨酸413。为了测试体内丝氨酸413磷酸化的作用，我们现在生产了其中丝氨酸413突变为丙氨酸的敲入小鼠。令人惊讶地，我们发现在这些突变小鼠中，三种不同形式的突触前依赖PKA的长期可塑性是正常的。此外，我们观察到，与RIM1αKO小鼠相比，含有丝氨酸413取代的RIM1敲入小鼠表现出正常的学习能力。 RIM1α的丝氨酸413突变的影响的缺乏不是由于RIM2α的补偿，因为携带丝氨酸413取代和RIM2α缺失的小鼠仍表现出正常的长期突触前可塑性。因此，RIM1α的丝氨酸413的磷酸化对于体内PKA依赖性的长期突触前可塑性不是必需的，这表明尽管长期的突触前可塑性对RIM1α有依赖性，但PKA的作用机制却不同。

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