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 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 [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 GABA_A, is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied.