biostudies-literatureUnknown6Martenson JSNCATS NIH HHSNIMH NIH HHSNINDS NIH HHSNIH HHSNIGMS NIH HHSGABA_A receptor (GABA_AR) pentamers are assembled from a pool of 19 subunits, and variety in subunit combinations diversifies GABA_AR 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 GABA_AR assembly in vivo. Here, we reveal assembly rules of native GABA_AR complexes that explain GABA_AR subunit subcellular distributions using mice and <i>Xenopus laevis</i> oocytes. First, α subunits possess intrinsic signals to segregate into distinct pentamers. Second, γ2 is essential for GABA_AR assembly with Neuroligin-2 (NL2) and GARLHs, which localize GABA_ARs at synapses. Third, δ suppresses α6 synaptic localization by preventing assembly with GARLHs/NL2. These findings establish the first molecular model for combinatorial GABA_AR assembly in vivo and reveal an assembly pathway regulating GABA_AR synaptic localization.eLifehttps://www.ebi.ac.uk/biostudies/studies/S-EPMC5577914biostudies-literatureAssembly rules for GABA_A receptor complexes in the brain.PMC5577914TL1 TR000141U24 NS050606R56 MH077939F30 MH099742T32 GM007205U01 MH104984R01 MH077939U42 OD012210F30 MH113299Albrecht DTomita SYamasaki TMartenson JSChaudhury NHfalseAssembly rules for GABA_A receptor complexes in the brain.GABA_A receptor (GABA_AR) pentamers are assembled from a pool of 19 subunits, and variety in subunit combinations diversifies GABA_AR 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 GABA_AR assembly in vivo. Here, we reveal assembly rules of native GABA_AR complexes that explain GABA_AR subunit subcellular distributions using mice and <i>Xenopus laevis</i> oocytes. First, α subunits possess intrinsic signals to segregate into distinct pentamers. Second, γ2 is essential for GABA_AR assembly with Neuroligin-2 (NL2) and GARLHs, which localize GABA_ARs at synapses. Third, δ suppresses α6 synaptic localization by preventing assembly with GARLHs/NL2. These findings establish the first molecular model for combinatorial GABA_AR assembly in vivo and reveal an assembly pathway regulating GABA_AR synaptic localization.2017-01-01T00:00:00Z2017 Aug2022-02-09T08:44:31.652Z2019-03-26T23:39:49ZS-EPMC55779142881665310.7554/eLife.27443