GABAA receptors: function, physiology and involvement in anesthesia

ABSTRACT
The γ-aminobutyric acid type A (GABAA) receptor is an ionotropic inhibitory ion channel. Inhibition mediated by
GABAA receptors sets the level of activity in the brain, whereas in individual cells it determines the propensity
of a cell to fire an action potential in response to excitatory input. The GABAA receptor is a major target for
intravenous anesthetics and numerous endogenous compounds including neuroactive steroids. This project
will investigate how combinations of endogenous and clinical compounds affect the functioning of the native
GABAA receptor, and initiate the onset and offset of anesthesia. Specifically, we will: i) explore the kinetic and
energetic aspects of activation and modulation of native synaptic and extrasynaptic GABAA receptors by
clinically-relevant compounds; ii) determine the involvement of endogenous neurosteroids in the clinical actions
of intravenous anesthetics to test the hypothesis that normal physiological changes in steroid levels modify
responses to anesthetics; iii) probe ways for controllable recovery from anesthesia; and iv) test the feasibility of
using partial allosteric agonists of the GABAA receptor as safe, mild sedatives.

Grant Number: 5R35GM140947-05
NIH Institute/Center: NIH
Principal Investigator: GUSTAV AKK