Abstract

PROJECT 1 Modulation of GABA-A or NMDA receptors underlies the anesthetic actions of most clinically used general anesthetics. In the central nervous system, enhancement of GABA-A receptor function increases inhibitory neurotransmission and inhibition of NMDA receptor function decreases excitatory neurotransmission. Anesthetic steroids enhance the actions of GABA at GABA-A receptors. Steroids containing negatively charged groups inhibit GABAergic neurotransmission. NMDA receptors are modulated, either positively or negatively, by steroids that contain negatively charged groups. Thus, understanding the actions of steroids at these receptors is important for understanding the clinical effects of the steroid class of anesthetics. The three specific aims of this project are focused on gaining new knowledge of the molecular details of the interactions of steroids with GABA-A and NMDA receptors. Synthetic chemistry will be performed to prepare novel analogues of anesthetic steroids for structure-activity relationships (SAR) studies. Electrophysiological, binding, and behavioral assayswill be used for evaluation of the compounds.
Specific aim 1 addresses the importance of the steroid ring system for anesthetic steroid effects at GABA-A and NMDA receptors.
In specific aim 2, anesthetic steroid analogues containing fluorescent groups will be prepared to: 1) investigate how steroids access their binding sites in the transmembrane domains of GABA-A receptors;and 2) investigate the entry and distribution of anesthetic steroids in brain cells.
Specific aim 3 will investigate the molecular basis for the enantioselectivity of anesthetic steroid action at GABA-A receptors. The long term goals of this project are to use the methods of medicinal chemistry to obtain new pharmacological tools for investigationof the effects of steroids at GABA-A and NMDA receptors. Ultimately, this information could lead to the discovery of new anesthetic, anticonvulsant, anxiolytic and sedative hypnotic drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM047969-18
Application #
7896815
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
18
Fiscal Year
2009
Total Cost
$363,810
Indirect Cost

  Institution

Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Budelier, Melissa M; Cheng, Wayland W L; Bergdoll, Lucie et al. (2017) Photoaffinity labeling with cholesterol analogues precisely maps a cholesterol-binding site in voltage-dependent anion channel-1. J Biol Chem 292:9294-9304
Jiang, Xiaoping; Shu, Hong-Jin; Krishnan, Kathiresan et al. (2016) A clickable neurosteroid photolabel reveals selective Golgi compartmentalization with preferential impact on proximal inhibition. Neuropharmacology 108:193-206
Li, Ping; Akk, Gustav (2015) Synaptic-type ?1?2?2L GABAA receptors produce large persistent currents in the presence of ambient GABA and anesthetic drugs. Mol Pharmacol 87:776-81
Zhou, Yu; Xia, Xiao-Ming; Lingle, Christopher J (2015) Cadmium-cysteine coordination in the BK inner pore region and its structural and functional implications. Proc Natl Acad Sci U S A 112:5237-42
Eaton, Megan M; Bracamontes, John; Shu, Hong-Jin et al. (2014) ?-aminobutyric acid type A ?4, ?2, and ? subunits assemble to produce more than one functionally distinct receptor type. Mol Pharmacol 86:647-56
Bracamontes, John R; Li, Ping; Akk, Gustav et al. (2014) Mutations in the main cytoplasmic loop of the GABA(A) receptor ?4 and ? subunits have opposite effects on surface expression. Mol Pharmacol 86:20-7
Zorumski, Charles F; Mennerick, Steven; Izumi, Yukitoshi (2014) Acute and chronic effects of ethanol on learning-related synaptic plasticity. Alcohol 48:1-17
Linsenbardt, Andrew J; Taylor, Amanda; Emnett, Christine M et al. (2014) Different oxysterols have opposing actions at N-methyl-D-aspartate receptors. Neuropharmacology 85:232-42
Jafurulla, Md; Rao, Bhagyashree D; Sreedevi, Sugunan et al. (2014) Stereospecific requirement of cholesterol in the function of the serotonin1A receptor. Biochim Biophys Acta 1838:158-63
Chen, Zi-Wei; Wang, Cunde; Krishnan, Kathiresan et al. (2014) 11-trifluoromethyl-phenyldiazirinyl neurosteroid analogues: potent general anesthetics and photolabeling reagents for GABAA receptors. Psychopharmacology (Berl) 231:3479-91

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