The pentameric chloride channel BEST1 is activated by extracellular GABA
Year: 2025
Type: article
Abstract: 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 B G-protein coupled receptors and the pentameric GABA A 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 2+ ], 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 A , is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied. Significance Statement γ -aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the central nervous system. Extracellular GABA is primarily sensed by GABA B G-protein coupled receptors, and GABA A pentameric chloride channels. We show that the chloride channel bestrophin-1 (BEST1) is also activated by extracellular GABA. The application of GABA, but not glycine or other endogenous molecules we tested, markedly potentiates chloride currents through the channel. Structural studies combined with electrophysiology and other functional studies reveal the mechanism of GABA activation. GABA binding within the outer entryway of the channel allosterically controls its gate, ‘the neck’. Molecular interactions with GABA resemble those in GABA A receptors, despite a lack of homology between the channels. The physiological significance of GABA-activation in BEST1 remains to be studied.
Authors: Swati Pant, Stephanie W. Tam, Stephen B. Long
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: G289723095, G2898555083, G3756646923, G422055439, G4582736256, G7229056886, G7371786123, NCCAT: National Center for CryoEM Access and Training, Structural and functional studies of calcium activated chloride channel Bestrophin-1, Cancer Center Support Grant, Mechanisms of Ion Channels and Enzymatic Membrane Proteins
OpenAlex ID: W4409580582