Partial Agonism of Taurine at Gamma-Containing Native and Recombinant GABA(A) Receptors

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 GABA(A)-receptors (GABA(A)R) gated by taurine are not yet known. We determined taurine potency and efficacy relative to GABA at different types of recombinant GABA(A)R occurring in central histaminergic neurons of the mouse hypothalamic tuberomamillary nucleus (TMN) which controls arousal. At binary α(1/2)β(1/3) receptors taurine was as efficient as GABA, whereas incorporation of the γ(1/2) subunit reduced taurine efficacy to 60–90% of GABA. The mutation γ(2F77I), 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 α(x)β(1)δ-GABA(A)R, we generated a chimeric γ(2) subunit carrying the δ subunit motif around F77 (MTVFLH). At α(1/2)β(1)γ(2(MTVFLH)) receptors taurine became a super-agonist, similar to δ-containing ternary receptors, but remained a partial agonist at β(3)-containing receptors. In conclusion, using site-directed mutagenesis we found structural determinants of taurine’s partial agonism at γ-containing GABA(A) receptors. Our study sheds new light on the β(1) subunit conferring the widest range of taurine-efficacies modifying GABA(A)R function under (patho)physiological conditions.