Different Subtypes of GABA-A Receptors Are Expressed in Human, Mouse and Rat T Lymphocytes

Suresh K Mendu,Bryndis Birnir,Zhe Jin,Amol Bhandage,Kjetil Tasken

doi:10.1371/journal.pone.0042959

Abstract

γ-aminobutyric acid (GABA) is the most prominent neuroinhibitory transmitter in the brain, where it activates neuronal GABA-A receptors (GABA-A channels) located at synapses and outside of synapses. The GABA-A receptors are primary targets of many clinically useful drugs. In recent years, GABA has been shown to act as an immunomodulatory molecule. We have examined in human, mouse and rat CD4+ and CD8+ T cells which subunit isoforms of the GABA-A channels are expressed. The channel physiology and drug specificity is dictated by the GABA-A receptor subtype, which in turn is determined by the subunit isoforms that make the channel. There were 5, 8 and 13 different GABA-A subunit isoforms identified in human, mouse and rat CD4+ and CD8+ T cells, respectively. Importantly, the γ2 subunit that imposes benzodiazepine sensitivity on the GABA-A receptors, was only detected in the mouse T cells. Immunoblots and immunocytochemistry showed abundant GABA-A channel proteins in the T cells from all three species. GABA-activated whole-cell transient and tonic currents were recorded. The currents were inhibited by picrotoxin, SR95531 and bicuculline, antagonists of GABA-A channels. Clearly, in both humans and rodents T cells, functional GABA-A channels are expressed but the subtypes vary. It is important to bear in mind the interspecies difference when selecting the appropriate animal models to study the physiological role and pharmacological properties of GABA-A channels in CD4+ and CD8+ T cells and when selecting drugs aimed at modulating the human T cells function.

Highlights

The GABA-A receptor is an ion channel that opens when caminobutyric acid (GABA) binds to its binding site on the receptor complex
Differential expression of GABA-A channel subunit mRNAs in human, rat and mouse CD4+ and CD8+ T cells and Jurkat cells Here we examined whether the 19 different GABA-A channel subunit mRNAs were present in CD4+ and CD8+ T cells from rats (Wistar), mice (C57BL/6J) and humans as well as in a human CD4+ T cell line, the Jurkat cells
Primers specific for each GABAA channel subunit (Table 1) were verified using the appropriate brain cDNA samples from humans, rats or mice. In both CD4+ and CD8+ T cells isolated from mesenteric lymph nodes from Wistar rats, 13 GABA-A channel subunit mRNAs were detected (Fig. 1A and Table 2)

Summary

Introduction

The GABA-A receptor is an ion channel that opens when caminobutyric acid (GABA) binds to its binding site on the receptor complex. GABA is the most important neuroinhibitory transmitter. It is released from neuronal presynaptic terminals and activates the GABA-A channels located at the postsynaptic site [1]. GABA in low, submicromolar concentrations is present around the neurons where it activates high-affinity GABA-A channels located outside of synapses [1,2]. These channels are called extrasynaptic GABA-A channels [3]. The focus over the years has been on the GABA-A channels in the brain, there is growing evidence indicating a significant, physiological function of GABA and GABA-A channels in a number of non-neuronal tissue [4]. Components of the GABA signaling systems have been identified in cells of the immune system [5,6,7,8,9,10,11,12,13]

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Conclusion