Partial Agonism of Taurine at Gamma-Containing Native and Recombinant GABAA Receptors

Olaf Kletke,Hanns Hatt,Andrea May,Guenter Gisselmann,Olga A Sergeeva,Pascale Chavis

doi:10.1371/journal.pone.0061733

Olaf Kletke, Hanns Hatt + Show 4 more

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https://doi.org/10.1371/journal.pone.0061733

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Abstract

Taurine is a semi-essential sulfonic acid found at high concentrations in plasma and mammalian tissues which regulates osmolarity, ion channel activity and glucose homeostasis. The structural requirements of GABAA-receptors (GABAAR) gated by taurine are not yet known. We determined taurine potency and efficacy relative to GABA at different types of recombinant GABAAR occurring in central histaminergic neurons of the mouse hypothalamic tuberomamillary nucleus (TMN) which controls arousal. At binary α1/2β1/3 receptors taurine was as efficient as GABA, whereas incorporation of the γ1/2 subunit reduced taurine efficacy to 60–90% of GABA. The mutation γ2F77I, which abolishes zolpidem potentiation, significantly reduced taurine efficacy at recombinant and native receptors compared to the wild type controls. As taurine was a full- or super- agonist at recombinant αxβ1δ-GABAAR, we generated a chimeric γ2 subunit carrying the δ subunit motif around F77 (MTVFLH). At α1/2β1γ2(MTVFLH) receptors taurine became a super-agonist, similar to δ-containing ternary receptors, but remained a partial agonist at β3-containing receptors. In conclusion, using site-directed mutagenesis we found structural determinants of taurine’s partial agonism at γ-containing GABAA receptors. Our study sheds new light on the β1 subunit conferring the widest range of taurine-efficacies modifying GABAAR function under (patho)physiological conditions.

Highlights

Taurine (2-aminoethane sulfonic acid) is very abundant in plasma and mammalian tissues including brain, where it regulates osmolarity, ion channel activity, neuronal growth and metabolism [1,2,3,4]
Histaminergic neurons from the tuberomamillary nucleus (TMN) of the hypothalamus were selected for the present study as functional and structural features of their GABAA receptors were previously characterised with the a1, a2, a5, b1, b3, c1, c2, e, but not d subunit- transcripts being regularly detected [25,26,27,28]
Previous studies have shown that the putative assembly signals, the residues determining selective co-assemblies of a-b or a-c2, in GABAARs [36] as well as in nicotinic acetylcholine receptors [37], are adjacent to, or identical to the residues that form the ligand-binding site

Summary

Introduction

Taurine (2-aminoethane sulfonic acid) is very abundant in plasma and mammalian tissues including brain, where it regulates osmolarity, ion channel activity, neuronal growth and metabolism [1,2,3,4] It remains controversial whether taurine can be called ‘‘neurotransmitter’’: some but not other studies reported accumulation of taurine in the synaptic vesicles [5;6] and action potentialdependent release [7]. If molecular structure of taurine binding site at different glycine receptor types are known [13;14], taurine binding site at GABAA receptor was not yet systematically analysed.

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