Partial Agonism of Taurine at Gamma-Containing Native

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 a1/2b1/3 receptors taurine was as efficient as GABA, whereas incorporation of the c1/2 subunit reduced taurine efficacy to 60–90 % of GABA. The mutation c2F77I, 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 axb1d-GABAAR, we generated a chimeric c2 subunit carrying the d subunit motif around F77 (MTVFLH). At a1/2b1c2(MTVFLH) receptors taurine became a super-agonist, similar to d-containing ternary receptors, but remained a partial agonist at b3-containing receptors. In conclusion, using site-directed mutagenesis we found structural determinants of taurine’s partial agonism at c-containing GABAA receptors. Our study sheds new light on the b1 subunit conferring the widest range of taurine-efficacies modifying GABAAR function under (patho)physiologica