GARLH Family Proteins Stabilize GABAA Receptors at Synapses

Ionotropic neurotransmitter receptors mediate fast synaptic transmission by functioning as ligand-gated ion channels. Fast inhibitory transmission in the brain is mediated mostly by ionotropic GABAA receptors (GABAARs), but their essential components for synaptic localization remain unknown. Here, we identify putative auxiliary subunits of GABAARs, which we term GARLHs, consisting of LH4 and LH3 proteins. LH4 forms a stable tripartite complex with GABAARs and neuroligin-2 in the brain. Moreover, LH4 is required for the synaptic localization of GABAARs and inhibitory synaptic transmission in the hippocampus. Our findings propose GARLHs as the first identified auxiliary subunits for anion channels. These findings provide new insights into the regulation of inhibitory transmission and the molecular constituents of native anion channels in vivo. •The γ2-containing GABAARs form a tripartite complex with LH4 and neuroligin-2•GARLHs are GABAAR putative auxiliary subunits consisting of LH3 and LH4•The GABAAR γ2 subunit regulates protein expressions of LH4 and neuroligin-2•GARLH is required for the synaptic GABAAR localization and inhibitory transmission Yamasaki et al. report GARLH family proteins as putative auxiliary subunits of GABAARs in vivo. GARLH forms a tripartite complex with GABAARs and neuroligin-2 and regulates the synaptic localization of GABAARs and inhibitory synaptic transmission.