Assembly rules for GABA A receptor complexes in the brain.

GABAA receptor (GABAA R) pentamers are assembled from a pool of 19 subunits, and variety in subunit combinations diversifies GABAA R 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 GABAA R assembly in vivo. Here, we reveal assembly rules of native GABAA R complexes that explain GABAA R subunit subcellular distributions using mice and Xenopus laevis oocytes. First, α subunits possess intrinsic signals to segregate into distinct pentamers. Second, γ2 is essential for GABAA R assembly with Neuroligin-2 (NL2) and GARLHs, which localize GABAA Rs at synapses. Third, δ suppresses α6 synaptic localization by preventing assembly with GARLHs/NL2. These findings establish the first molecular model for combinatorial GABAA R assembly in vivo and reveal an assembly pathway regulating GABAA R synaptic localization.