The pentameric chloride channel BEST1 is activated by extracellular GABA

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 {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 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 channels extracellular side and determine the mechanism by which GABA binding induces opening of the channels central gate. This same gate 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, is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied. Significance Statement{gamma}-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the central nervous system. Extracellular GABA is primarily sensed by GABAB G-protein coupled receptors, and GABAA 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 GABAA receptors, despite a lack of homology between the channels. The physiological significance of GABA-activation in BEST1 remains to be studied.