TY - JOUR
T1 - Assembly rules for GABAA receptor complexes in the brain
AU - Martenson, James S.
AU - Yamasaki, Tokiwa
AU - Chaudhury, Nashid H.
AU - Albrecht, David
AU - Tomita, Susumu
N1 - Funding Information:
The authors thank Pietro De Camilli, Angus Nairn, Peter Aronson, Michael Higley, Houqing Yu, Ania Puszynska and members of the Tomita lab for helpful discussions. We thank Dr. Erwin Sigel for original GABAAR concatenated constructs, Dr. Janet L Fisher for GABAAR a6 cDNA, Dr. Louis Reichardt for sharing transgenic Cre mice under the Gabra6 promoter through the MMRRC, Dr. Bernhard Luscher and Dr. Jamie Maguire for conditional g2 mice and d mice, respectively, through the Jackson laboratory. The monoclonal antibodies were obtained from the University of California Davis/ National Institutes of Health NeuroMab Facility (NIH U24NS050606). ST is supported by NIH MH077939, MH104984 and Yale University, JSM is supported by NIH F30 MH099742 and the NIH T32GM007205, TY is supported by the Uehara Memorial Foundation, and NHC is supported by NIH F30 MH113299, CTSA TL1TR000141 and NIH/NIGMS T32 GM007205.
Publisher Copyright:
© Martenson et al.
PY - 2017/8/17
Y1 - 2017/8/17
N2 - GABAA receptor (GABAAR) pentamers are assembled from a pool of 19 subunits, and variety in subunit combinations diversifies GABAAR 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 GABAAR assembly in vivo. Here, we reveal assembly rules of native GABAAR complexes that explain GABAAR subunit subcellular distributions using mice and Xenopus laevis oocytes. First, a subunits possess intrinsic signals to segregate into distinct pentamers. Second, γ2 is essential for GABAAR assembly with Neuroligin-2 (NL2) and GARLHs, which localize GABAARs at synapses. Third, δ suppresses α6 synaptic localization by preventing assembly with GARLHs/NL2. These findings establish the first molecular model for combinatorial GABAAR assembly in vivo and reveal an assembly pathway regulating GABAAR synaptic localization.
AB - GABAA receptor (GABAAR) pentamers are assembled from a pool of 19 subunits, and variety in subunit combinations diversifies GABAAR 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 GABAAR assembly in vivo. Here, we reveal assembly rules of native GABAAR complexes that explain GABAAR subunit subcellular distributions using mice and Xenopus laevis oocytes. First, a subunits possess intrinsic signals to segregate into distinct pentamers. Second, γ2 is essential for GABAAR assembly with Neuroligin-2 (NL2) and GARLHs, which localize GABAARs at synapses. Third, δ suppresses α6 synaptic localization by preventing assembly with GARLHs/NL2. These findings establish the first molecular model for combinatorial GABAAR assembly in vivo and reveal an assembly pathway regulating GABAAR synaptic localization.
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U2 - 10.7554/eLife.27443
DO - 10.7554/eLife.27443
M3 - Article
C2 - 28816653
AN - SCOPUS:85029152967
SN - 2050-084X
VL - 6
JO - eLife
JF - eLife
M1 - e27443
ER -