GARLH Family Proteins Stabilize GABA 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 GABA receptors (GABARs), but their essential components for synaptic localization remain unknown. Here, we identify putative auxiliary subunits of GABARs, which we term GARLHs, consisting of LH4 and LH3 proteins. LH4 forms a stable tripartite complex with GABARs and neuroligin-2 in the brain. Moreover, LH4 is required for the synaptic localization of GABARs 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.