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.
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.
|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|
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|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|
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