Pant Swati, Tam Stephanie W, Long Stephen B
Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Graduate Program in Biochemistry and Structural Biology, Cell and Developmental Biology, and Molecular Biology, Weill Cornell Medicine Graduate School of Medical Sciences, New York, USA.
bioRxiv. 2024 Nov 22:2024.11.22.624909. doi: 10.1101/2024.11.22.624909.
Bestrophin 1 (BEST1) is chloride channel expressed in the eye, central nervous system (CNS), and other tissues in the body. A link between BEST1 and the principal inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been proposed. The most appreciated receptors for extracellular GABA are the GABA G-protein coupled receptors and the pentameric GABA chloride channels, both of which have fundamental roles in the CNS. Here, we demonstrate that BEST1 is directly activated by GABA. Through functional studies and atomic-resolution structures of human and chicken BEST1, we identify a GABA binding site on the channel's extracellular side and determine the mechanism by which GABA binding induces opening of the channel's central gate. This same gate is activated by intracellular [Ca], indicating that BEST1 is controlled by ligands from both sides of the membrane. The studies demonstrate that BEST1, which shares no structural homology with GABA, is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied.
贝斯特罗芬1（BEST1）是一种在眼睛、中枢神经系统（CNS）和身体其他组织中表达的氯离子通道。有人提出BEST1与主要抑制性神经递质γ-氨基丁酸（GABA）之间存在联系。细胞外GABA最受关注的受体是GABA G蛋白偶联受体和五聚体GABA氯离子通道，两者在中枢神经系统中都起着基本作用。在此，我们证明BEST1可被GABA直接激活。通过对人和鸡BEST1的功能研究及原子分辨率结构分析，我们在通道的细胞外侧鉴定出一个GABA结合位点，并确定了GABA结合诱导通道中央门打开的机制。同一扇门可被细胞内的[Ca]激活，这表明BEST1受来自膜两侧的配体控制。这些研究表明，与GABA没有结构同源性的BEST1是一种GABA激活的氯离子通道。这一发现的生理意义仍有待研究。
