Anesthetic effects on γ-aminobutyric acid A receptors: not just on your nerves.

1013 May 2013 I N this current issue of Anesthesiology, Xiang et al.1 describe the effects of volatile anesthetic activation of type A γ-amino butyric acid (GABAA) receptors expressed on airway epithelial cells. It has long been appreciated that a key mechanism in the action of general anesthetics in the brain involves the anesthetics’ allosteric potentiation of GABA on GABAA receptors, thereby augmenting this inhibitory neurotransmitter system. However, the demonstration that GABAA receptors are expressed extra-neuronally by a wide variety of cell types and modulate other important physiologic processes is a recent revelation. Although the bronchodilatory effects of volatile anesthetics have been clinically appreciated for many years, the signaling mechanisms by which this occurs in the lung are not fully known. The current study raises our awareness that anesthetics, via activation of GABAA receptors, may be having many effects on multiple cell types in the lung that not only mediate bronchodilation, but also effect immunomodulation and mucus production by epithelial cells. The emerging discovery of GABAA receptors on many peripheral cells raises important questions regarding the unrecognized effects of anesthetics on peripheral cellular processes. The current study follows the seminal discovery (by these same authors) that multiple components of a GABAergic signaling system (GABAA receptors and the enzyme that synthesizes GABA [glutamic acid decarboxylase]) are expressed in airway epithelium and play an important role in the modulation of mucus production.2 In the current study, the authors focus on the alveolar type II epithelial (ATII) cells as they are also known to participate in immunomodulatory pulmonary processes (including specialized surfactant production and cytokine elaboration) which have important implications in inflammatory diseases of the lung such as asthma. With regard to the ATII cells, Xiang et al. advance our understanding of the GABAergic system in these cells by demonstrating the expression of multiple typical and atypical protein subunits of GABAA receptors collectively from human cultured alveolar epithelial type II (A549) cells as well as in situ human peripheral lung sections. Additionally, they elegantly demonstrate on these human cultured ATII cells classical currents in response to exogenous GABA with positive allosteric modulation by isoflurane and sevoflurane. Most interestingly, isoflurane impairs the basal expression of a key proinflammatory enzyme, cyclooxygenase-2, presumably via decreased calcium entry following GABAA receptormediated membrane depolarization. Opening of GABAA channels in ATII cells favors chloride efflux and depolarization in contrast to mature neurons where opening of GABAA channels favors chloride influx and membrane hyperpolarization due to differing electrochemical gradients in these cell types. These findings suggest a possible mechanism of anesthetics’ antiinflammatory effects not only in airway epithelial cells, but also on a host of other nonneuronal cells (including T lymphocytes) that have recently been found to express GABAA receptors. It should be noted that the phenotype of GABAA subunits that Xiang et al. report on human ATII cells is consistent with subunit expression observed when GABAA receptors are found outside the neuronal synaptic cleft (i.e., “extrasynaptic GABAA receptors”). These extrasynaptic GABAA receptors within the central nervous system seem to be limited to only Anesthetic Effects on γ-Aminobutyric Acid A Receptors