The pentameric chloride channel BEST1 is activated by extracellular GABA

• 成果类型: Article
• 署名作者: Pant, Swati; Tam, Stephanie W.; Long, Stephen B.
• 署名单位: Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8737
• DOI: 10.1073/pnas.2424474122
• 发表日期: 2025-04-22
• 关键词: vitelliform macular dystrophy; bestrophin-1; astrocytes; release; expression; insights; disease; islets; FAMILY

摘要

Bestrophin-1 (BEST1) is a chloride channel expressed in the eye and other tissues of the body. A link between BEST1 and the principal inhibitory neurotransmitter gamma- aminobutyric acid (GABA) has been proposed. The most appreciated receptors for extracellular GABA are the GABAB G-protein-coupled receptors and the pentameric GABAA chloride channels, both of which have fundamental roles in the central nervous system. 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 stabilizes opening of the channel's central gate. This same gate, the neck, is activated by intracellular [Ca2+], indicating that BEST1 is controlled by ligands from both sides of the membrane. The studies demonstrate that BEST1, which shares no structural homology with GABAA receptors, is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied.