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GABA 受体辅助亚基调节中脑被盖核末梢的 Cav2.3 介导的释放。

GABA receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals.

机构信息

Institute of Science and Technology Austria (IST Austria), Klosterneuburg, Austria.

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

出版信息

Elife. 2021 Apr 29;10:e68274. doi: 10.7554/eLife.68274.

DOI:10.7554/eLife.68274
PMID:33913808
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8121548/
Abstract

The synaptic connection from medial habenula (MHb) to interpeduncular nucleus (IPN) is critical for emotion-related behaviors and uniquely expresses R-type Ca channels (Cav2.3) and auxiliary GABA receptor (GBR) subunits, the K-channel tetramerization domain-containing proteins (KCTDs). Activation of GBRs facilitates or inhibits transmitter release from MHb terminals depending on the IPN subnucleus, but the role of KCTDs is unknown. We therefore examined the localization and function of Cav2.3, GBRs, and KCTDs in this pathway in mice. We show in heterologous cells that KCTD8 and KCTD12b directly bind to Cav2.3 and that KCTD8 potentiates Cav2.3 currents in the absence of GBRs. In the rostral IPN, KCTD8, KCTD12b, and Cav2.3 co-localize at the presynaptic active zone. Genetic deletion indicated a bidirectional modulation of Cav2.3-mediated release by these KCTDs with a compensatory increase of KCTD8 in the active zone in KCTD12b-deficient mice. The interaction of Cav2.3 with KCTDs therefore scales synaptic strength independent of GBR activation.

摘要

中脑缰核（MHb）到脚间核（IPN）的突触连接对于与情绪相关的行为至关重要，并且独特地表达 R 型钙通道（Cav2.3）和辅助 GABA 受体（GBR）亚基、K 通道四聚体化结构域蛋白（KCTDs）。GBR 的激活根据 IPN 亚核促进或抑制 MHb 末梢递质的释放，但 KCTDs 的作用尚不清楚。因此，我们在小鼠中检查了该途径中 Cav2.3、GBR 和 KCTDs 的定位和功能。我们在异源细胞中表明，KCTD8 和 KCTD12b 直接与 Cav2.3 结合，并且 KCTD8 在没有 GBR 的情况下增强 Cav2.3 电流。在 IPN 的前脑区域，KCTD8、KCTD12b 和 Cav2.3 在突触前活性区共定位。遗传缺失表明这些 KCTDs 对 Cav2.3 介导的释放进行双向调制，在 KCTD12b 缺陷型小鼠中，活性区中的 KCTD8 代偿性增加。因此，Cav2.3 与 KCTDs 的相互作用独立于 GBR 激活调节突触强度。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e29b/8121548/a31dd7ff5ad0/elife-68274-fig8-figsupp1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e29b/8121548/53b4a256e45f/elife-68274-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e29b/8121548/c3dc2ea9ad48/elife-68274-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e29b/8121548/b37bdbfb6bc7/elife-68274-fig2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e29b/8121548/9e78acaf4d6d/elife-68274-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e29b/8121548/6b29718b40a1/elife-68274-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e29b/8121548/3560609e42c6/elife-68274-fig3-figsupp2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e29b/8121548/b091166ce917/elife-68274-fig6-figsupp1.jpg
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