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Pin1 依赖性信号传导通过调节神经连接蛋白 2/gephyrin 相互作用对 γ-氨基丁酸能传递产生负面影响。

Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction.

作者信息

Antonelli Roberta, Pizzarelli Rocco, Pedroni Andrea, Fritschy Jean-Marc, Del Sal Giannino, Cherubini Enrico, Zacchi Paola

机构信息

Department of Neuroscience, International School for Advanced Studies (SISSA), via Bonomea 265, 34136 Trieste, Italy.

Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

出版信息

Nat Commun. 2014 Oct 9;5:5066. doi: 10.1038/ncomms6066.

DOI:10.1038/ncomms6066
PMID:25297980
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4197815/
Abstract

The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis-trans isomerase Pin1. This signalling cascade negatively regulates NL2's ability to interact with gephyrin at GABAergic post-synaptic sites. As a consequence, enhanced accumulation of NL2, gephyrin and GABAA receptors was detected at GABAergic synapses in the hippocampus of Pin1-knockout mice (Pin1-/-) associated with an increase in amplitude of spontaneous GABAA-mediated post-synaptic currents. Our results suggest that Pin1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NL2/gephyrin interaction.

摘要

细胞黏附分子神经连接蛋白2（NL2）选择性地定位于γ-氨基丁酸能（GABAergic）突触，在那里它与突触后致密物中的支架蛋白gephyrin相互作用。然而，这种相互作用对GABAergic突触形成和可塑性的作用尚不清楚。在这里，我们证明内源性NL2在其独特的S714-P共有位点发生脯氨酸定向磷酸化，导致肽基脯氨酰顺反异构酶Pin1的募集。这种信号级联反应负向调节NL2在GABAergic突触后位点与gephyrin相互作用的能力。因此，在Pin1基因敲除小鼠（Pin1-/-）的海马体中，GABAergic突触处检测到NL2、gephyrin和GABAA受体的积累增强，这与自发GABAA介导的突触后电流幅度增加有关。我们的结果表明，Pin1依赖性信号传导代表了一种通过调节NL2/gephyrin相互作用来调节GABAergic传递的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e2e/4214426/723340e4201b/ncomms6066-f10.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e2e/4214426/22e11794d2bc/ncomms6066-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e2e/4214426/723340e4201b/ncomms6066-f10.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e2e/4214426/5b69b29657ea/ncomms6066-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e2e/4214426/853dc81cd108/ncomms6066-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e2e/4214426/22e11794d2bc/ncomms6066-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e2e/4214426/723340e4201b/ncomms6066-f10.jpg

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