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Mapping General Anesthetic Sites in Heteromeric ?-Aminobutyric Acid Type A Receptors Reveals a Potential For Targeting Receptor Subtypes

Forman, Stuart A. MD, PhD; Miller, Keith W. DPhil

doi: 10.1213/ANE.0000000000001368
Neuroscience and Neuroanesthesiology: Narrative Review Article

IV general anesthetics, including propofol, etomidate, alphaxalone, and barbiturates, produce important actions by enhancing γ-aminobutyric acid type A (GABAA) receptor activation. In this article, we review scientific studies that have located and mapped IV anesthetic sites using photoaffinity labeling and substituted cysteine modification protection. These anesthetics bind in transmembrane pockets between subunits of typical synaptic GABAA receptors, and drugs that display stereoselectivity also show remarkably selective interactions with distinct interfacial sites. These results suggest strategies for developing new drugs that selectively modulate distinct GABAA receptor subtypes.

Published ahead of print May 10, 2016.

From the Department of Anesthesia Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Published ahead of print May 10, 2016.

Accepted for publication March 18, 2016.

Funding: National Institute of General Medical Sciences (GM058448, GM089745), and National Institutes of Health (NIH) P41 RR-01081.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Stuart A. Forman, MD, PhD, Department of Anesthesia Critical Care and Pain Medicine, Massachusetts General Hospital, 5 Fruit St, Boston, MA 02114. Address e-mail to saforman@partners.org.

© 2016 International Anesthesia Research Society