Smalley, JL; Cho, N; Ng, SFJ; Choi, C; Lemons, AHS; Chaudry, S; Bope, CE; ... Moss, SJ; + view all Smalley, JL; Cho, N; Ng, SFJ; Choi, C; Lemons, AHS; Chaudry, S; Bope, CE; Dengler, JS; Zhang, C; Rasband, MN; Davies, PA; Moss, SJ; - view fewer (2023) Spectrin-beta 2 facilitates the selective accumulation of GABAA receptors at somatodendritic synapses. Communications Biology , 6 , Article 11. 10.1038/s42003-022-04381-x.

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Abstract

Fast synaptic inhibition is dependent on targeting specific GABAAR subtypes to dendritic and axon initial segment (AIS) synapses. Synaptic GABAARs are typically assembled from α1-3, β and γ subunits. Here, we isolate distinct GABAARs from the brain and interrogate their composition using quantitative proteomics. We show that α2-containing receptors co-assemble with α1 subunits, whereas α1 receptors can form GABAARs with α1 as the sole α subunit. We demonstrate that α1 and α2 subunit-containing receptors co-purify with distinct spectrin isoforms; cytoskeletal proteins that link transmembrane proteins to the cytoskeleton. β2-spectrin was preferentially associated with α1-containing GABAARs at dendritic synapses, while β4-spectrin was associated with α2-containing GABAARs at AIS synapses. Ablating β2-spectrin expression reduced dendritic and AIS synapses containing α1 but increased the number of synapses containing α2, which altered phasic inhibition. Thus, we demonstrate a role for spectrins in the synapse-specific targeting of GABAARs, determining the efficacy of fast neuronal inhibition.

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