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