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

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Nature Communications Pub Date : 2024-09-14 DOI:10.1038/s41467-024-52039-5

Jiali Wang, Aaron P. Owji, Alec Kittredge, Zada Clark, Yu Zhang, Tingting Yang

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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.

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

Bestrophin-1（Best1）是一种阴离子通道，与威胁视力的视网膜变性通道病有遗传联系。在这里，我们确定了 Best1 与谷氨酸脱羧酶（GAD65 和 GAD67）两种异构体之间的相互作用，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，并解析了与 GABA 结合的 Best1 的结构。GAD65和GAD67都能促进Best1介导的Cl-电流，但只有GAD65能显著增强Best1对谷氨酸和GABA的通透性，而GAD67对谷氨酸和GABA没有影响。GABA 可与 Best1 的细胞外位点结合，并在纳米摩尔浓度水平上刺激 Best1 介导的 Cl- 电流。在视网膜色素上皮细胞中证明了 GAD65 作为细胞类型特异性结合伙伴和 Best1 促进剂的生理作用。我们的研究结果揭示了 Best1 的关键调节因子，并为 Bestrophin 通道与谷氨酸代谢酶之间形成的膜转运代谢子网络提供了信息。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.