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Multiple Functional Neurosteroid Binding Sites on GABAA Receptors

bioRxiv, ISSN: 2692-8205
2018
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Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    2
    • Citation Indexes
      2
      • CrossRef
        2

Article Description

Neurosteroids are endogenous modulators of neuronal excitability and nervous system development and are being developed as anesthetic agents and treatments for psychiatric diseases. While GABA receptors are the primary molecular targets of neurosteroid action, the structural details of neurosteroid binding to these proteins remain ill-defined. We synthesized neurosteroid analogue photolabeling reagents in which the photolabeling groups were placed at three positions around the neurosteroid ring structure, enabling identification of binding sites and mapping of neurosteroid orientation within these sites. Using middle-down mass spectrometry, we identified three clusters of photolabeled residues representing three distinct neurosteroid binding sites in the human αβGABA receptor. Novel intrasubunit binding sites were identified within the transmembrane helical bundles of both the α and β subunits, adjacent to the extracellular domains. An intersubunit site in the interface between the β(+) and α(-) subunits of the GABA receptor pentamer was also identified. Computational docking studies of neurosteroid to the three sites predicted critical residues contributing to neurosteroid interaction with the GABA receptors. Electrophysiological studies based on these predictions indicate that both the α intrasubunit and β-α intersubunit sites are critical for neurosteroid action.

Bibliographic Details

Zi Wei Chen; John R. Bracamontes; Melissa M. Budelier; Allison L. Germann; Daniel J. Shin; Brad Manion; Wayland W.L. Cheng; Gustav Akk; Douglas F. Covey; Alex S. Evers; Krishnan Kathiresan; Ming Xing Qian; David E. Reichert

Cold Spring Harbor Laboratory

Biochemistry, Genetics and Molecular Biology; Agricultural and Biological Sciences; Immunology and Microbiology; Neuroscience; Pharmacology, Toxicology and Pharmaceutics

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