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CaMKII 通过神经肽基因表达和神经肽囊泡的轴突靶向控制神经调节。

CaMKII controls neuromodulation via neuropeptide gene expression and axonal targeting of neuropeptide vesicles.

机构信息

Department of Clinical Genetics, Center for Neurogenomics and Cognitive Research (CNCR), University Medical Center Amsterdam, Amsterdam, the Netherlands.

Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, Amsterdam, the Netherlands.

出版信息

PLoS Biol. 2020 Aug 10;18(8):e3000826. doi: 10.1371/journal.pbio.3000826. eCollection 2020 Aug.

DOI:10.1371/journal.pbio.3000826
PMID:32776935
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7447270/
Abstract

Ca2+/calmodulin-dependent kinase II (CaMKII) regulates synaptic plasticity in multiple ways, supposedly including the secretion of neuromodulators like brain-derived neurotrophic factor (BDNF). Here, we show that neuromodulator secretion is indeed reduced in mouse α- and βCaMKII-deficient (αβCaMKII double-knockout [DKO]) hippocampal neurons. However, this was not due to reduced secretion efficiency or neuromodulator vesicle transport but to 40% reduced neuromodulator levels at synapses and 50% reduced delivery of new neuromodulator vesicles to axons. αβCaMKII depletion drastically reduced neuromodulator expression. Blocking BDNF secretion or BDNF scavenging in wild-type neurons produced a similar reduction. Reduced neuromodulator expression in αβCaMKII DKO neurons was restored by active βCaMKII but not inactive βCaMKII or αCaMKII, and by CaMKII downstream effectors that promote cAMP-response element binding protein (CREB) phosphorylation. These data indicate that CaMKII regulates neuromodulation in a feedback loop coupling neuromodulator secretion to βCaMKII- and CREB-dependent neuromodulator expression and axonal targeting, but CaMKIIs are dispensable for the secretion process itself.

摘要

钙/钙调蛋白依赖性激酶 II（CaMKII）通过多种方式调节突触可塑性，据称包括脑源性神经营养因子（BDNF）等神经调质的分泌。在这里，我们表明，神经调质的分泌确实在小鼠的 α- 和 βCaMKII 缺失（αβCaMKII 双敲除 [DKO]）海马神经元中减少。然而，这不是由于分泌效率降低或神经调质囊泡运输减少，而是由于突触处神经调质水平降低了 40%，新的神经调质囊泡向轴突的运输减少了 50%。αβCaMKII 的耗竭大大降低了神经调质的表达。在野生型神经元中阻断 BDNF 分泌或 BDNF 清除也会产生类似的减少。通过活性βCaMKII 而不是非活性βCaMKII 或αCaMKII，以及通过促进 cAMP 反应元件结合蛋白（CREB）磷酸化的 CaMKII 下游效应物，可恢复 αβCaMKII DKO 神经元中减少的神经调质表达。这些数据表明，CaMKII 通过反馈回路调节神经调质，将神经调质的分泌与βCaMKII 和 CREB 依赖性神经调质表达和轴突靶向偶联，但 CaMKII 对于分泌过程本身是可有可无的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bcd/7447270/80031a8b7f9e/pbio.3000826.g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bcd/7447270/80031a8b7f9e/pbio.3000826.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bcd/7447270/1c4ef3e3a90a/pbio.3000826.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bcd/7447270/d0496093c45a/pbio.3000826.g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8bcd/7447270/80031a8b7f9e/pbio.3000826.g008.jpg

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