Structural basis of neurosteroid anesthetic action on GABAA receptors

Chen, Qiang; Wells, Marta M.; Arjunan, Palaniappa; Tillman, Tommy S.; Cohen, Aina E.; Xu, Yan; Tang, Pei

doi:10.1038/s41467-018-06361-4

Structural basis of neurosteroid anesthetic action on GABAA receptors

Journal Article · Fri Sep 28 00:00:00 EDT 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-06361-4· OSTI ID:1529559

^[1]; Wells, Marta M. ^[1]; Arjunan, Palaniappa ^[1]; Tillman, Tommy S. ^[1]; Cohen, Aina E. ^[2]; ^[1]; Tang, Pei ^[1]

Univ. of Pittsburgh, PA (United States)
SLAC National Accelerator Lab., Menlo Park, CA (United States)

Type A γ-aminobutyric acid receptors (GABA_ARs) are inhibitory pentameric ligand-gated ion channels in the brain. Many anesthetics and neurosteroids act through binding to the GABA_AR transmembrane domain (TMD), but the structural basis of their actions is not well understood and no resting-state GABA_AR structure has been determined. Here, we report crystal structures of apo and the neurosteroid anesthetic alphaxalone-bound desensitized chimeric α1GABA_AR (ELIC-α1GABA_AR). The chimera retains the functional and pharmacological properties of GABA_ARs, including potentiation, activation and desensitization by alphaxalone. The apo-state structure reveals an unconventional activation gate at the intracellular end of the pore. The desensitized structure illustrates molecular determinants for alphaxalone binding to an inter-subunit TMD site. These structures suggest a plausible signaling pathway from alphaxalone binding at the bottom of the TMD to the channel gate in the pore-lining TM2 through the TM1–TM2 linker. The study provides a framework to discover new GABA_AR modulators with therapeutic potential.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)

Grant/Contract Number:: AC02-76SF00515; W-31109-ENG-38

OSTI ID:: 1529559

Alternate ID(s):: OSTI ID: 1506500

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 9; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Binding site location on GABA _A receptors determines whether mixtures of intravenous general anaesthetics interact synergistically or additively in vivo Kent, Daniel E.; Savechenkov, Pavel Y.; Bruzik, Karol S. British Journal of Pharmacology, Vol. 176, Issue 24 https://doi.org/10.1111/bph.14843	journal	December 2019

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