Cargando…

Anaesthetic Impairment of Immune Function Is Mediated via GABA(A) Receptors

BACKGROUND: GABA(A) 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 [1]. Recent work has shown that Cys-loop receptors are present on immune cells, but their p...

Descripción completa

Detalles Bibliográficos
Autores principales: Wheeler, Daniel W., Thompson, Andrew J., Corletto, Federico, Reckless, Jill, Loke, Justin C. T., Lapaque, Nicolas, Grant, Andrew J., Mastroeni, Pietro, Grainger, David J., Padgett, Claire L., O'Brien, John A., Miller, Nigel G. A., Trowsdale, John, Lummis, Sarah C. R., Menon, David K., Beech, John S.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044756/
https://www.ncbi.nlm.nih.gov/pubmed/21390329
http://dx.doi.org/10.1371/journal.pone.0017152
_version_ 1782198775794630656
author Wheeler, Daniel W.
Thompson, Andrew J.
Corletto, Federico
Reckless, Jill
Loke, Justin C. T.
Lapaque, Nicolas
Grant, Andrew J.
Mastroeni, Pietro
Grainger, David J.
Padgett, Claire L.
O'Brien, John A.
Miller, Nigel G. A.
Trowsdale, John
Lummis, Sarah C. R.
Menon, David K.
Beech, John S.
author_facet Wheeler, Daniel W.
Thompson, Andrew J.
Corletto, Federico
Reckless, Jill
Loke, Justin C. T.
Lapaque, Nicolas
Grant, Andrew J.
Mastroeni, Pietro
Grainger, David J.
Padgett, Claire L.
O'Brien, John A.
Miller, Nigel G. A.
Trowsdale, John
Lummis, Sarah C. R.
Menon, David K.
Beech, John S.
author_sort Wheeler, Daniel W.
collection PubMed
description BACKGROUND: GABA(A) 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 [1]. 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 [2]. 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 [3]–[6]. As many anaesthetics act via GABA(A) receptors [7], 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 GABA(A) receptors constructed of α1, α4, β2, γ1 and/or δ 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 GABA(A) receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABA(A) receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin. SIGNIFICANCE: Our results show that functional GABA(A) receptors are present on monocytes with properties similar to CNS GABA(A) 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 GABA(A) receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABA(A) 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.
format Text
id pubmed-3044756
institution National Center for Biotechnology Information
language English
publishDate 2011
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-30447562011-03-09 Anaesthetic Impairment of Immune Function Is Mediated via GABA(A) Receptors Wheeler, Daniel W. Thompson, Andrew J. Corletto, Federico Reckless, Jill Loke, Justin C. T. Lapaque, Nicolas Grant, Andrew J. Mastroeni, Pietro Grainger, David J. Padgett, Claire L. O'Brien, John A. Miller, Nigel G. A. Trowsdale, John Lummis, Sarah C. R. Menon, David K. Beech, John S. PLoS One Research Article BACKGROUND: GABA(A) 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 [1]. 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 [2]. 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 [3]–[6]. As many anaesthetics act via GABA(A) receptors [7], 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 GABA(A) receptors constructed of α1, α4, β2, γ1 and/or δ 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 GABA(A) receptor antagonists bicuculline and picrotoxin, but not enhanced by the positive modulator diazepam. The anaesthetic drugs propofol and thiopental, which can act via GABA(A) receptors, impaired monocyte function in classic immunological chemotaxis and phagocytosis assays, an effect reversed by bicuculline and picrotoxin. SIGNIFICANCE: Our results show that functional GABA(A) receptors are present on monocytes with properties similar to CNS GABA(A) 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 GABA(A) receptors inhibits normal monocyte behaviour. The data also suggest a potential solution: monocyte GABA(A) 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. Public Library of Science 2011-02-24 /pmc/articles/PMC3044756/ /pubmed/21390329 http://dx.doi.org/10.1371/journal.pone.0017152 Text en Wheeler et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wheeler, Daniel W.
Thompson, Andrew J.
Corletto, Federico
Reckless, Jill
Loke, Justin C. T.
Lapaque, Nicolas
Grant, Andrew J.
Mastroeni, Pietro
Grainger, David J.
Padgett, Claire L.
O'Brien, John A.
Miller, Nigel G. A.
Trowsdale, John
Lummis, Sarah C. R.
Menon, David K.
Beech, John S.
Anaesthetic Impairment of Immune Function Is Mediated via GABA(A) Receptors
title Anaesthetic Impairment of Immune Function Is Mediated via GABA(A) Receptors
title_full Anaesthetic Impairment of Immune Function Is Mediated via GABA(A) Receptors
title_fullStr Anaesthetic Impairment of Immune Function Is Mediated via GABA(A) Receptors
title_full_unstemmed Anaesthetic Impairment of Immune Function Is Mediated via GABA(A) Receptors
title_short Anaesthetic Impairment of Immune Function Is Mediated via GABA(A) Receptors
title_sort anaesthetic impairment of immune function is mediated via gaba(a) receptors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044756/
https://www.ncbi.nlm.nih.gov/pubmed/21390329
http://dx.doi.org/10.1371/journal.pone.0017152
work_keys_str_mv AT wheelerdanielw anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT thompsonandrewj anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT corlettofederico anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT recklessjill anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT lokejustinct anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT lapaquenicolas anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT grantandrewj anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT mastroenipietro anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT graingerdavidj anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT padgettclairel anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT obrienjohna anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT millernigelga anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT trowsdalejohn anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT lummissarahcr anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT menondavidk anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors
AT beechjohns anaestheticimpairmentofimmunefunctionismediatedviagabaareceptors