Bright, Damian P; Schulte, Clemens; Halff, Elise F; Lumb, Michael J; Kittler, Josef T; Maric, Hans M; Smart, Trevor G; (2025) Nexilin regulates cell surface expression of extrasynaptic GABAA receptors by binding to actin. Neuropharmacology , Article 110633. 10.1016/j.neuropharm.2025.110633. (In press).

Text 1-s2.0-S0028390825003417-main.pdf - Accepted Version Access restricted to UCL open access staff until 13 August 2026. Download (9MB)

Abstract

Controlling cell-surface expression of GABAA receptors is vital for homeostatic maintenance of inhibitory transmission within the brain. Here, we describe a novel interaction between the actin-binding protein nexilin and extrasynaptic γ2 subunit-containing GABAA receptors. Pulldowns, array-based mapping, and deep-mutational scanning indicate that nexilin binding depends on a distinct motif conserved within the C-terminal ends of GABAA γ-subunit intracellular loops. Manipulation of nexilin levels in hippocampal neurons leads to correlated changes in GABA-mediated currents and GABAA receptor surface expression. This regulation is critically dependent upon nexilin binding to actin, since deletion of the actin-binding domain ablates the effects on GABAA receptor expression. Nexilin upregulation leads to an increase in synaptic GABAA receptor numbers, whilst down-regulation has no effect on synaptic currents, suggesting that nexilin is particularly important only for extrasynaptic γ2-GABAA receptors. However, altering nexilin expression also impacts upon inhibitory synaptic plasticity, possibly reflecting the altered availability of receptors anchored in the extrasynaptic membrane. Nexilin control of extrasynaptic γ2-GABAA receptor expression levels represents a new regulatory mechanism for both tonic and phasic inhibition.

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