The pentameric chloride channel BEST1 is activated by extracellular GABA

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(16)

Published: April 18, 2025

Bestrophin-1 (BEST1) is a chloride channel expressed in the eye and other tissues of body. A link between BEST1 principal inhibitory neurotransmitter γ -aminobutyric acid (GABA) has been proposed. The most appreciated receptors for extracellular GABA are B G-protein-coupled pentameric channels, both which have fundamental roles central nervous system. Here, we demonstrate that directly activated by GABA. Through functional studies atomic-resolution structures human chicken BEST1, identify binding site on channel’s side determine mechanism stabilizes opening gate. This same gate, “the neck,” intracellular [Ca 2+ ], indicating controlled ligands from sides membrane. shares no structural homology with receptors, GABA-activated channel. physiological implications this finding remain to be studied.

Language: Английский

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Bestrophin1-mediated GABA release activates large chloride currents to generate epileptiform events in the entorhinal cortex

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 19, 2025

Abstract The mechanisms that lead to the onset of a focal seizure are still not understood. We used well-established 4-aminopyridine (4AP) ictogenesis model analyze epileptiform discharges in entorhinal cortex rodents maintained vitro . Simultaneous field potential and patch-clamp recordings demonstrated 100 µM 4AP elicited periodic large chloride currents both principal neurons GABAergic interneurons steadily matched with population spikes. These spike-associated ( PSACCs ) survived glutamate glycine receptor blockade were abolished by GABA A antagonists blocking synaptic neurotransmitters release. Antagonist astrocyte bestrophin-1 channels inhibited prevented occurrence seizure-like events mouse slices isolated guinea pig brain. propose bestrophin-1-induced release likely triggered astrocytes promotes all subtypes current is responsible for interictal spikes establishes conditions generation events.

Language: Английский

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The pentameric chloride channel BEST1 is activated by extracellular GABA

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

Abstract Bestrophin 1 (BEST1) is chloride channel expressed in the eye, central nervous system (CNS), and other tissues body. A link between BEST1 principal inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been proposed. The most appreciated receptors for extracellular GABA are B G-protein coupled pentameric channels, both of which have fundamental roles CNS. Here, we demonstrate that directly activated by GABA. Through functional studies atomic-resolution structures human chicken BEST1, identify a binding site on channel’s side determine mechanism induces opening gate. This same gate intracellular [Ca 2+ ], indicating controlled ligands from sides membrane. shares no structural homology with , GABA-activated channel. physiological implications this finding remain to be studied. Significance Statement γ -aminobutyric system. Extracellular primarily sensed receptors, channels. We show bestrophin-1 also application GABA, but not glycine or endogenous molecules tested, markedly potentiates currents through Structural combined electrophysiology reveal activation. within outer entryway allosterically controls its gate, ‘the neck’. Molecular interactions resemble those despite lack significance GABA-activation remains

Language: Английский

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Chloride fluxes and GABA release sustain inhibition in the CNS: The role for Bestrophin 1 anion channels

Acta Physiologica, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

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