Yo GABAA GABAA: How the Structure of Human GABAA Receptor Affects the Action of Anesthetics

Abstract

Propofol, a powerful anesthetic, can be used safely in medical settings, but proves deadly when used recreationally. Propofol binds to the GABAA receptor, which consists of an integral ion channel protein embedded in the membrane of neurons in the brain that is activated by the neurotransmitter molecule gamma‐aminobutyric acid, or GABA. When propofol binds to the GABAA receptor, a conformational change occurs, holding the neurotransmitter GABA in its binding site and keeping the ion channel open. This allows more chloride ions to diffuse into the cell. Resting potential becomes more negative, so even with the diffusion of Na+ ions during nerve stimulation, the threshold cannot be reached and the action potential is not generated. Since the neurons cannot communicate normally, a person given propofol remains unconscious. The lower part of the GABAA receptor, located in the cytoplasm of a neuron, has an unidentified molecular structure. Phe 393 variants in the A and D chains prevent propofol from acting on the GABAA receptor. The DSHA SMART (Students Modeling A Research Topic) Team modeled the similar nicotinic receptor using 3D printing technology to better understand the structure of the GABAA receptor. A greater understanding of the structure of the GABAA receptor and the role of the Phe 393 variants in the action of propofol can lead to the development of more effective anesthetics.Support or Funding InformationThe MSOE Center for BioMolecular Modeling would like to acknowledge and thank the National Institutes of Health Science Education Partnership Award (NIH‐SEPA 1R25OD010505‐01) and the National Institutes of Health Clinical and Translational Science Award (NIH‐CTSA UL1RR031973) for their support in funding the 2017–2018 SMART Team Team program.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.