Assembly rules for GABA receptor complexes in the brain.

GABA receptor (GABAR) pentamers are assembled from a pool of 19 subunits, and variety in subunit combinations diversifies GABAR functions to tune brain activity. Pentamers with distinct subunit compositions localize differentially at synaptic and non-synaptic sites to mediate phasic and tonic inhibition, respectively. Despite multitudes of theoretical permutations, limited subunit combinations have been identified in the brain. Currently, no molecular model exists for combinatorial GABAR assembly in vivo. Here, we reveal assembly rules of native GABAR complexes that explain GABAR subunit subcellular distributions using mice and oocytes. First, α subunits possess intrinsic signals to segregate into distinct pentamers. Second, γ2 is essential for GABAR assembly with Neuroligin-2 (NL2) and GARLHs, which localize GABARs at synapses. Third, δ suppresses α6 synaptic localization by preventing assembly with GARLHs/NL2. These findings establish the first molecular model for combinatorial GABAR assembly in vivo and reveal an assembly pathway regulating GABAR synaptic localization.