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Assembly rules for GABAA receptor complexes in the brain.

eLife | Aug 17, 2017

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, α 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.

Pubmed ID: 28816653 RIS Download

Mesh terms: Animals | Brain Chemistry | Mice | Neural Inhibition | Oocytes | Protein Binding | Protein Multimerization | Protein Transport | Receptors, GABA-A | Xenopus laevis

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Associated grants

  • Agency: NIMH NIH HHS, Id: F30 MH099742
  • Agency: NIMH NIH HHS, Id: F30 MH113299
  • Agency: NCATS NIH HHS, Id: TL1 TR000141
  • Agency: NINDS NIH HHS, Id: U24 NS050606
  • Agency: NIMH NIH HHS, Id: R01 MH077939
  • Agency: NIGMS NIH HHS, Id: T32 GM007205
  • Agency: NIMH NIH HHS, Id: R56 MH077939
  • Agency: NIMH NIH HHS, Id: U01 MH104984

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