by Daniel W. Wheeler, Andrew J. Thompson, Federico Corletto, Jill Reckless, Justin C. T. Loke, Nicolas Lapaque, Andrew J. Grant, Pietro Mastroeni, David J. Grainger, Claire L. Padgett, John A. O'Brien, Nigel G. A. Miller, John Trowsdale, Sarah C. R. Lummis, David K. Menon, John S. Beech
GABAA receptors are members of the Cys-loop family of neurotransmitter receptors, proteins which are responsible for fast synaptic transmission, and are the site of action of wide range of drugs . Recent work has shown that Cys-loop receptors are present on immune cells, but their physiological roles and the effects of drugs that modify their function in the innate immune system are currently unclear . We are interested in how and why anaesthetics increase infections in intensive care patients; a serious problem as more than 50% of patients with severe sepsis will die –. As many anaesthetics act via GABAA receptors , the aim of this study was to determine if these receptors are present on immune cells, and could play a role in immunocompromising patients. Principal Findings
We demonstrate, using RT-PCR, that monocytes express GABAA receptors constructed of a1, a4, ß2, ?1 and/or d subunits. Whole cell patch clamp electrophysiological studies show that GABA can activate these receptors, resulting in the opening of a chloride-selective channel; activation is inhibited by the GABAA receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABAA receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin. Significance
Our results show that functional GABAA receptors are present on monocytes with properties similar to CNS GABAA receptors. The functional data provide a possible explanation as to why chronic propofol and thiopental administration can increase the risk of infection in critically ill patients: their action on GABAA receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABAA receptors are insensitive to diazepam, thus the use of benzodiazepines as an alternative anesthetising agent may be advantageous where infection is a life threatening problem.