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GAD65 调节 Best1 作为 GABA 受体和神经递质传导通道的功能。

GAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel.

机构信息

Department of Ophthalmology, Columbia University, New York, NY, USA.

出版信息

Nat Commun. 2024 Sep 14;15(1):8051. doi: 10.1038/s41467-024-52039-5.

DOI:10.1038/s41467-024-52039-5
PMID:39277606
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11401937/
Abstract

Bestrophin-1 (Best1) is an anion channel genetically linked to vision-threatening retinal degenerative channelopathies. Here, we identify interactions between Best1 and both isoforms of glutamic acid decarboxylases (GAD65 and GAD67), elucidate the distinctive influences of GAD65 and GAD67 on Best1's permeability to various anions/neurotransmitters, discover the functionality of Best1 as a γ-Aminobutyric acid (GABA) type A receptor, and solve the structure of GABA-bound Best1. GAD65 and GAD67 both promote Best1-mediated Cl currents, but only GAD65 drastically enhances the permeability of Best1 to glutamate and GABA, for which GAD67 has no effect. GABA binds to Best1 on an extracellular site and stimulates Best1-mediated Cl currents at the nano-molar concentration level. The physiological role of GAD65 as a cell type-specific binding partner and facilitator of Best1 is demonstrated in retinal pigment epithelial cells. Together, our results reveal critical regulators of Best1 and inform a network of membrane transport metabolons formed between bestrophin channels and glutamate metabolic enzymes.

摘要

Bestrophin-1（Best1）是一种阴离子通道，与威胁视力的视网膜退行性通道病有遗传关联。在这里，我们确定了 Best1 与谷氨酸脱羧酶（GAD65 和 GAD67）两种同工型之间的相互作用，阐明了 GAD65 和 GAD67 对 Best1 对各种阴离子/神经递质通透性的独特影响，发现了 Best1 作为γ-氨基丁酸（GABA）A 型受体的功能，并解决了 GABA 结合的 Best1 结构。GAD65 和 GAD67 都促进 Best1 介导的 Cl 电流，但只有 GAD65 极大地增强了 Best1 对谷氨酸和 GABA 的通透性，而 GAD67 则没有影响。GABA 结合到 Best1 的细胞外位点，并在纳摩尔浓度水平刺激 Best1 介导的 Cl 电流。GAD65 在视网膜色素上皮细胞中作为细胞类型特异性结合伴侣和 Best1 促进剂的生理作用得到了证明。总之，我们的结果揭示了 Best1 的关键调节剂，并阐明了由 Bestrophin 通道和谷氨酸代谢酶之间形成的膜转运代谢物网络。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/6abbaf9f484f/41467_2024_52039_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/30a8f51e0e0c/41467_2024_52039_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/5b71d043bd41/41467_2024_52039_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/fce6d1176c1b/41467_2024_52039_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/7a039899918d/41467_2024_52039_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/6f946d12f328/41467_2024_52039_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/ee0703d7d60f/41467_2024_52039_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/6abbaf9f484f/41467_2024_52039_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/30a8f51e0e0c/41467_2024_52039_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/5b71d043bd41/41467_2024_52039_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/fce6d1176c1b/41467_2024_52039_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/7a039899918d/41467_2024_52039_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/6f946d12f328/41467_2024_52039_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/ee0703d7d60f/41467_2024_52039_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/317a/11401937/6abbaf9f484f/41467_2024_52039_Fig7_HTML.jpg

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本文引用的文献

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Bestrophin-2 and glutamine synthetase form a complex for glutamate release.Bestrophin-2 和谷氨酰胺合成酶形成复合物以释放谷氨酸。
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Structures and gating mechanisms of human bestrophin anion channels.
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