Rapid Action of 17 -Estradiol on Kainate-Induced Currents in Hippocampal Neurons Lacking Intracellular Estrogen Receptors

Abstract

17{beta}-Estradiol can potentiate kainate-induced currents in isolated hippocampal CA1 neurons. The action of estrogen was rapid in onset, steroid and stereospecific, and reversible. The potentiation could be mimicked by 8-bromo-cAMP, an activator of protein kinase A. As the hippocampus expresses both isoforms of the intracellular estrogen receptor (ER{alpha} and ER{beta}), the role of ERs in the rapid action of 17{beta}-estradiol remains elusive. Here we report that the rapid action of 17{beta}-estradiol is independent from the classical ER activation in the modulation of membrane excitability. Under whole cell voltage clamp recording configuration, 17{beta}-estradiol-induced potentiation was observed in both wild-type and the ER{alpha} gene knockout mice. The perfusion or incubation of ICI 182,780, which blocks both ER{alpha} and ER{beta}, did not affect estrogen potentiation in either group. Further study showed that adenosine 3',5'-cyclic-monophosphothioate Rp-isomer, a specific inhibitor of protein kinase A, completely blocked the potentiation observed with the application of 17{beta}-estradiol in ER{alpha} gene knockout mice. Our results provide evidence that a distinct estrogen-binding site exists, which appears to be coupled to {alpha}-amino-3-hydroxyl-5-methyl-4-isoxazole proprionic acid/kainate receptors by a cAMP-dependent phosphorylation process.