Recent Advances in Understanding Fundamental Mechanisms of Volatile General Anesthetic Action

Tao      Zhang; Konda   S.   Reddy; Jonas   S.   Johansson

Abstract

Over 20 million patients in the United States alone each year receive a general anesthetic for a surgical procedure. Nevertheless, molecular mechanisms of volatile general anesthetic action remain poorly understood. The favored sites of action in the central nervous system are currently a variety of plasma membrane proteins including the Cys-loop superfamily of ligand-gated ion channels and the N-methyl-D-aspartate receptor, because volatile general anesthetics are able to alter the ion conducting properties of these proteins. Volatile general anesthetics are only capable of relatively weak interactions with macromolecular targets, precluding the use of conventional radioligand binding assays for identifying central nervous system targets. In order to overcome this significant technical obstacle, other approaches to monitor volatile general anesthetic binding have been developed that rely on 19F-nuclear magnetic resonance spectroscopy, photoaffinity labeling with halothane, fluorescence spectroscopy, and isothermal titration calorimetry. These techniques have allowed the determination of volatile general anesthetic dissociation constants for a number of different protein complexes. The effect of a bound volatile general anesthetic on protein stability, flexibility, and overall structure has been investigated in recent years, and the results suggest fundamental mechanisms whereby these important clinical compounds reversibly alter protein function.

Keywords: Volatile general anesthetic, ligand-gated ion channel, binding affinity, protein stability, protein flexibility, general anesthetic action

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