Glycine receptor in rat hippocampal and spinal cord neurons as a molecular target for rapid actions of 17-β-estradiol

Glycine receptors (GlyRs) play important roles in regulating hippocampal neural network activity and spinal nociception. Here we show that, in cultured rat hippocampal (HIP) and spinal dorsal horn (SDH) neurons, 17-β-estradiol (E(2)) rapidly and reversibly reduced the peak amplitude of whole-cell glycine-activated currents (I(Gly)). In outside-out membrane patches from HIP neurons devoid of nuclei, E(2 )similarly inhibited I(Gly), suggesting a non-genomic characteristic. Moreover, the E(2 )effect on I(Gly )persisted in the presence of the calcium chelator BAPTA, the protein kinase inhibitor staurosporine, the classical ER (i.e. ERα and ERβ) antagonist tamoxifen, or the G-protein modulators, favoring a direct action of E(2 )on GlyRs. In HEK293 cells expressing various combinations of GlyR subunits, E(2 )only affected the I(Gly )in cells expressing α2, α2β or α3β subunits, suggesting that either α2-containing or α3β-GlyRs mediate the E(2 )effect observed in neurons. Furthermore, E(2 )inhibited the GlyR-mediated tonic current in pyramidal neurons of HIP CA1 region, where abundant GlyR α2 subunit is expressed. We suggest that the neuronal GlyR is a novel molecular target of E(2 )which directly inhibits the function of GlyRs in the HIP and SDH regions. This finding may shed new light on premenstrual dysphoric disorder and the gender differences in pain sensation at the CNS level.