The pentameric chloride channel BEST1 is activated by extracellular GABA Journal Article
| Authors: | Pant, S.; Tam, S. W.; Long, S. B. |
| Article Title: | The pentameric chloride channel BEST1 is activated by extracellular GABA |
| Abstract: | 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 γ-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. © 2025 the Author(s). |
| Keywords: | unclassified drug; genetics; nonhuman; animal; metabolism; animals; protein; calcium; tyrosine; central nervous system; chemistry; protein purification; gamma-aminobutyric acid; binding site; amino acid; isoleucine; binding sites; receptor; leucine; x ray crystallography; glutamic acid; sodium; electrophysiology; liposome; glycine; phenylalanine; potassium; chickens; activation; hek293 cells; 4 aminobutyric acid; neurotransmitter; chloride channel; 4 aminobutyric acid a receptor; channel gating; ion channel gating; receptors, gaba-a; data processing; taurine; anion channel; humans; human; article; gallus gallus; chloride channels; whole cell patch clamp; gaba; hek293t cell line; flux assay; hek293s cell line; beta alanine; bestrophin; bestrophins; bestrophin 1; dextro serine; maxon; best1 protein, human; komagataella pastoris |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 122 |
| Issue: | 16 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2025-04-22 |
| Start Page: | e2424474122 |
| Language: | English |
| DOI: | 10.1073/pnas.2424474122 |
| PUBMED: | 40249777 |
| PROVIDER: | scopus |
| PMCID: | PMC12037058 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Stephen Long -- Source: Scopus |
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