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突触融合蛋白 11 促进了高尔基后囊泡中突触前信号复合物的组装。

Synaptotagmin-11 facilitates assembly of a presynaptic signaling complex in post-Golgi cargo vesicles.

机构信息

Department of Biomedicine, University of Basel, Basel, Switzerland.

Institute of Physiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

出版信息

EMBO Rep. 2024 Jun;25(6):2610-2634. doi: 10.1038/s44319-024-00147-0. Epub 2024 May 2.

DOI:10.1038/s44319-024-00147-0
PMID:38698221
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11169412/
Abstract

GABA receptors (GBRs), the G protein-coupled receptors for GABA, regulate synaptic transmission throughout the brain. A main synaptic function of GBRs is the gating of Cav2.2-type Ca channels. However, the cellular compartment where stable GBR/Cav2.2 signaling complexes form remains unknown. In this study, we demonstrate that the vesicular protein synaptotagmin-11 (Syt11) binds to both the auxiliary GBR subunit KCTD16 and Cav2.2 channels. Through these dual interactions, Syt11 recruits GBRs and Cav2.2 channels to post-Golgi vesicles, thus facilitating assembly of GBR/Cav2.2 signaling complexes. In addition, Syt11 stabilizes GBRs and Cav2.2 channels at the neuronal plasma membrane by inhibiting constitutive internalization. Neurons of Syt11 knockout mice exhibit deficits in presynaptic GBRs and Cav2.2 channels, reduced neurotransmitter release, and decreased GBR-mediated presynaptic inhibition, highlighting the critical role of Syt11 in the assembly and stable expression of GBR/Cav2.2 complexes. These findings support that Syt11 acts as a vesicular scaffold protein, aiding in the assembly of signaling complexes from low-abundance components within transport vesicles. This mechanism enables insertion of pre-assembled functional signaling units into the synaptic membrane.

摘要

GABA 受体（GBR）是 GABA 的 G 蛋白偶联受体，调节大脑中的突触传递。GBR 的主要突触功能是门控 Cav2.2 型钙通道。然而，形成稳定的 GBR/Cav2.2 信号复合物的细胞区室仍然未知。在这项研究中，我们证明了囊泡蛋白突触结合蛋白 11（Syt11）与辅助 GBR 亚基 KCTD16 和 Cav2.2 通道都结合。通过这两种相互作用，Syt11 将 GBR 和 Cav2.2 通道募集到高尔基后囊泡，从而促进 GBR/Cav2.2 信号复合物的组装。此外，Syt11 通过抑制组成型内化来稳定神经元质膜上的 GBR 和 Cav2.2 通道。Syt11 敲除小鼠的神经元中，突触前 GBR 和 Cav2.2 通道减少，神经递质释放减少，GBR 介导的突触前抑制减少，这突出表明 Syt11 在 GBR/Cav2.2 复合物的组装和稳定表达中具有关键作用。这些发现支持 Syt11 作为囊泡支架蛋白的作用，有助于在运输囊泡中低丰度成分的信号复合物的组装。这种机制允许预先组装的功能性信号单元插入突触膜。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4970/11169412/b3548a47ae6f/44319_2024_147_Fig11_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4970/11169412/fcee732745d0/44319_2024_147_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4970/11169412/d80bb863fcb6/44319_2024_147_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4970/11169412/6f3279f33b6c/44319_2024_147_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4970/11169412/c679ad6ebccf/44319_2024_147_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4970/11169412/261017f3d5e4/44319_2024_147_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4970/11169412/1e41b97d86be/44319_2024_147_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4970/11169412/6161e6545ff1/44319_2024_147_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4970/11169412/011e14f7221c/44319_2024_147_Fig10_ESM.jpg
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