Many clinically-used sedative and anesthetic agents act by modulating the function of the ?-aminobutyric acid type A (GABAA) receptor. The GABAA receptor is the major inhibitory transmitter-gated ion channel in the brain. Inhibition mediated by GABAA receptors sets the overall activity of the brain, while in individual cells it determines the propensity of a cell to fire an action potential in response to a given excitatory input. The GABAA receptor is also a target for numerous endogenous compounds including neuroactive steroids that can reduce the dosage requirement for intravenous anesthetics. The overall goal of this project is to investigate how various endogenous compounds and clinically used drugs modify the functioning of the GABAA receptor and initiate the onset and offset of anesthesia. Specifically, we will: i) examine the interactions between binding sites for various classes of GABAergic anesthetics; ii) test the hypothesis that modulation of tonic activity from synaptic-type GABAA receptors contributes to the actions of anesthetics; iii) determine the effects of anesthetic drug combinations on the function of native GABAA receptors; iv) test the hypothesis that endogenous steroids act as co-agonists enhancing the behavioral effects of clinically used GABAergic anesthetic drugs; and v) test the usefulness of competitive steroid-antagonists in promoting emergence from anesthesia.

Public Health Relevance

The GABAA receptor is a major target for intravenous anesthetics. The project will investigate how various endogenous and clinically-used sedative compounds affect the functioning of the GABAA receptor and control the onset and offset of anesthesia.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Falcon-Morales, Edgardo
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Cheng, Wayland W L; Chen, Zi-Wei; Bracamontes, John R et al. (2018) Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC. J Biol Chem 293:3013-3027
Cao, Lily Q; Montana, Michael C; Germann, Allison L et al. (2018) Enhanced GABAergic actions resulting from the coapplication of the steroid 3?-hydroxy-5?-pregnane-11,20-dione (alfaxalone) with propofol or diazepam. Sci Rep 8:10341
Germann, Allison L; Shin, Daniel J; Kuhrau, Christina R et al. (2018) High Constitutive Activity Accounts for the Combination of Enhanced Direct Activation and Reduced Potentiation in Mutated GABAA Receptors. Mol Pharmacol 93:468-476
Shin, Daniel J; Germann, Allison L; Johnson, Alexander D et al. (2018) Propofol Is an Allosteric Agonist with Multiple Binding Sites on Concatemeric Ternary GABAA Receptors. Mol Pharmacol 93:178-189
Sun, Min-Yu; Shu, Hong-Jin; Benz, Ann et al. (2018) Chemogenetic Isolation Reveals Synaptic Contribution of ? GABAA Receptors in Mouse Dentate Granule Neurons. J Neurosci 38:8128-8145
Akk, Gustav; Shin, Daniel J; Germann, Allison L et al. (2018) GABA Type A Receptor Activation in the Allosteric Coagonist Model Framework: Relationship between EC50 and Basal Activity. Mol Pharmacol 93:90-100
Shin, Daniel J; Germann, Allison L; Steinbach, Joe Henry et al. (2017) The Actions of Drug Combinations on the GABAA Receptor Manifest as Curvilinear Isoboles of Additivity. Mol Pharmacol 92:556-563
Chakrabarti, Sampurna; Qian, Mingxing; Krishnan, Kathiresan et al. (2016) Comparison of Steroid Modulation of Spontaneous Inhibitory Postsynaptic Currents in Cultured Hippocampal Neurons and Steady-State Single-Channel Currents from Heterologously Expressed ?1?2?2L GABA(A) Receptors. Mol Pharmacol 89:399-406
Bracamontes, John R; Akk, Gustav; Steinbach, Joe Henry (2016) Introduced Amino Terminal Epitopes Can Reduce Surface Expression of Neuronal Nicotinic Receptors. PLoS One 11:e0151071
Eaton, Megan M; Germann, Allison L; Arora, Ruby et al. (2016) Multiple Non-Equivalent Interfaces Mediate Direct Activation of GABAA Receptors by Propofol. Curr Neuropharmacol 14:772-80

Showing the most recent 10 out of 14 publications