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PKN1 通过激活神经元谷氨酸转运体来抑制 mGluR 依赖性沉默，从而促进突触成熟。

PKN1 promotes synapse maturation by inhibiting mGluR-dependent silencing through neuronal glutamate transporter activation.

机构信息

Education and Research Support Center, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan.

Division of Physiology, Faculty of Medicine, Saga University, Saga, Saga, 849-8501, Japan.

出版信息

Commun Biol. 2020 Nov 26;3(1):710. doi: 10.1038/s42003-020-01435-w.

DOI:10.1038/s42003-020-01435-w
PMID:33244074
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7691520/
Abstract

Abnormal metabotropic glutamate receptor (mGluR) activity could cause brain disorders; however, its regulation has not yet been fully understood. Here, we report that protein kinase N1 (PKN1), a protein kinase expressed predominantly in neurons in the brain, normalizes group 1 mGluR function by upregulating a neuronal glutamate transporter, excitatory amino acid transporter 3 (EAAT3), and supports silent synapse activation. Knocking out PKN1a, the dominant PKN1 subtype in the brain, unmasked abnormal input-nonspecific mGluR-dependent long-term depression (mGluR-LTD) and AMPA receptor (AMPAR) silencing in the developing hippocampus. mGluR-LTD was mimicked by inhibiting glutamate transporters in wild-type mice. Knocking out PKN1a decreased hippocampal EAAT3 expression and PKN1 inhibition reduced glutamate uptake through EAAT3. Also, synaptic transmission was immature; there were more silent synapses and fewer spines with shorter postsynaptic densities in PKN1a knockout mice than in wild-type mice. Thus, PKN1 plays a critical role in regulation of synaptic maturation by upregulating EAAT3 expression.

摘要

异常的代谢型谷氨酸受体（mGluR）活性可导致脑部疾病；然而，其调节机制尚未完全阐明。在此，我们报告称，蛋白激酶 N1（PKN1）是一种主要在大脑神经元中表达的蛋白激酶，通过上调神经元谷氨酸转运体兴奋性氨基酸转运体 3（EAAT3）来正常化 mGluR1 功能，并支持沉默突触的激活。敲除大脑中占主导地位的 PKN1 亚型 PKN1a，会使发育中的海马体中异常的输入非特异性 mGluR 依赖性长时程抑制（mGluR-LTD）和 AMPA 受体（AMPAR）沉默显现出来。野生型小鼠中抑制谷氨酸转运体可模拟 mGluR-LTD。敲除 PKN1a 会降低海马体中的 EAAT3 表达，而 PKN1 抑制则会通过 EAAT3 减少谷氨酸摄取。此外，突触传递不成熟；与野生型小鼠相比，PKN1a 敲除小鼠中存在更多的沉默突触和较短的突触后密度的棘突。因此，PKN1 通过上调 EAAT3 的表达在调节突触成熟中发挥关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/b3d8b4d6a987/42003_2020_1435_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/d3eaad1d2782/42003_2020_1435_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/b85d0d763d74/42003_2020_1435_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/05fa87a39b57/42003_2020_1435_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/8eff98ccab25/42003_2020_1435_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/47a1a518ec43/42003_2020_1435_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/b2ae4231923c/42003_2020_1435_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/849a6503f04b/42003_2020_1435_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/d5d19955c9e4/42003_2020_1435_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/b3d8b4d6a987/42003_2020_1435_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/d3eaad1d2782/42003_2020_1435_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/b85d0d763d74/42003_2020_1435_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/05fa87a39b57/42003_2020_1435_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/8eff98ccab25/42003_2020_1435_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/47a1a518ec43/42003_2020_1435_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/b2ae4231923c/42003_2020_1435_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/849a6503f04b/42003_2020_1435_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/d5d19955c9e4/42003_2020_1435_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ac13/7691520/b3d8b4d6a987/42003_2020_1435_Fig9_HTML.jpg

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