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通过小鼠大脑的镶嵌成像鉴定蛋白激酶A的亚型特异性亚细胞定位和功能。

Isoform-specific subcellular localization and function of protein kinase A identified by mosaic imaging of mouse brain.

作者信息

Ilouz Ronit, Lev-Ram Varda, Bushong Eric A, Stiles Travis L, Friedmann-Morvinski Dinorah, Douglas Christopher, Goldberg Jeffrey L, Ellisman Mark H, Taylor Susan S

机构信息

Department of Pharmacology, University of California, San Diego, La Jolla, United States.

Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California, San Diego, San Diego, United States.

出版信息

Elife. 2017 Jan 12;6:e17681. doi: 10.7554/eLife.17681.

DOI:10.7554/eLife.17681
PMID:28079521
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5300705/
Abstract

Protein kinase A (PKA) plays critical roles in neuronal function that are mediated by different regulatory (R) subunits. Deficiency in either the RIβ or the RIIβ subunit results in distinct neuronal phenotypes. Although RIβ contributes to synaptic plasticity, it is the least studied isoform. Using isoform-specific antibodies, we generated high-resolution large-scale immunohistochemical mosaic images of mouse brain that provided global views of several brain regions, including the hippocampus and cerebellum. The isoforms concentrate in discrete brain regions, and we were able to zoom-in to show distinct patterns of subcellular localization. RIβ is enriched in dendrites and co-localizes with MAP2, whereas RIIβ is concentrated in axons. Using correlated light and electron microscopy, we confirmed the mitochondrial and nuclear localization of RIβ in cultured neurons. To show the functional significance of nuclear localization, we demonstrated that downregulation of RIβ, but not of RIIβ, decreased CREB phosphorylation. Our study reveals how PKA isoform specificity is defined by precise localization.

摘要

蛋白激酶A（PKA）在由不同调节（R）亚基介导的神经元功能中发挥关键作用。RIβ或RIIβ亚基的缺陷会导致不同的神经元表型。尽管RIβ有助于突触可塑性，但它是研究最少的亚型。我们使用亚型特异性抗体生成了小鼠大脑的高分辨率大规模免疫组织化学镶嵌图像，这些图像提供了包括海马体和小脑在内的几个脑区的全局视图。这些亚型集中在离散的脑区，我们能够放大以显示亚细胞定位的不同模式。RIβ在树突中富集并与MAP2共定位，而RIIβ集中在轴突中。使用相关光镜和电镜，我们证实了RIβ在培养神经元中的线粒体和核定位。为了显示核定位的功能意义，我们证明RIβ的下调而非RIIβ的下调会降低CREB磷酸化。我们的研究揭示了PKA亚型特异性是如何由精确的定位所定义的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c58/5300705/5444ded9437e/elife-17681-fig8-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c58/5300705/5444ded9437e/elife-17681-fig8-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c58/5300705/df364d2bdf5f/elife-17681-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c58/5300705/612006916945/elife-17681-fig1-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c58/5300705/e3ba3eddb8a4/elife-17681-fig3-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c58/5300705/c5759a3c1469/elife-17681-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c58/5300705/168a8fe01e7c/elife-17681-fig7.jpg
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