Nexilin regulates cell surface expression of extrasynaptic GABA_A receptors by binding to actin

Controlling cell-surface expression of GABA_A 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 GABA_A 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 GABA_A γ-subunit intracellular loops. Manipulation of nexilin levels in hippocampal neurons leads to correlated changes in GABA-mediated currents and GABA_A receptor surface expression. This regulation is critically dependent upon nexilin binding to actin, since deletion of the actin-binding domain ablates the effects on GABA_A receptor expression. Nexilin upregulation leads to an increase in synaptic GABA_A receptor numbers, whilst down-regulation has no effect on synaptic currents, suggesting that nexilin is particularly important only for extrasynaptic γ2-GABA_A 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-GABA_A receptor expression levels represents a new regulatory mechanism for both tonic and phasic inhibition.