Abstract
The present study was conducted to characterize possible rapid effects of 17-β-estradiol on voltage-gated K+ channels in preoptic neurons and, in particular, to identify the mechanisms by which 17-β-estradiol affects the K+ channels. Whole-cell currents from dissociated rat preoptic neurons were studied by perforated-patch recording. 17-β-estradiol rapidly (within seconds) and reversibly reduced the K+ currents, showing an EC50 value of 9.7 µM. The effect was slightly voltage dependent, but independent of external Ca2+, and not sensitive to an estrogen-receptor blocker. Although 17-α-estradiol also significantly reduced the K+ currents, membrane-impermeant forms of estradiol did not reduce the K+ currents and other estrogens, testosterone and cholesterol were considerably less effective. The reduction induced by estradiol was overlapping with that of the KV-2-channel blocker r-stromatoxin-1. The time course of K+ current in 17-β-estradiol, with a time-dependent inhibition and a slight dependence on external K+, suggested an open-channel block mechanism. The properties of block were predicted from a computational model where 17-β-estradiol binds to open K+ channels. It was concluded that 17-β-estradiol rapidly reduces voltage-gated K+ currents in a way consistent with an open-channel block mechanism. This suggests a new mechanism for steroid action on ion channels.
Highlights
Sex steroids and their metabolites influence nervous function
Estradiol can be synthesized de novo from cholesterol in the brain [8] and testosterone is converted to estradiol by the cytochrome P450 aromatase, which is concentrated in areas involved in reproductive control such as the preoptic area [9], but is present in the hippocampus [8]
In the present study we aimed at clarifying the acute action of estradiol on voltage-gated K+ currents in neurons from the medial preoptic nucleus (MPN) of young male rats
Summary
Sex steroids and their metabolites influence nervous function. Besides playing important roles in the regulation of sexual behaviour [1], they affect differentiation of the nervous system, mood and emotional behaviour, responses to stress and cognitive functions [2,3,4,5]. In areas controlling sexual behaviour, such as the preoptic area, the local estradiol concentration is likely to reach even higher levels, which are toxic to other organs [1,10]. The rapid effects on male sexual behaviour suggest that besides ‘‘classical’’ mechanisms via intracellular estradiol receptors and gene transcription, nontranscriptional effects at the membrane level may be involved [6,7]. In the present study we aimed at clarifying the acute action of estradiol on voltage-gated K+ currents in neurons from the medial preoptic nucleus (MPN) of young male rats. A model with an open-channel block mechanism explained the experimentally observed effects of estradiol. We conclude that estradiol reduces delayed rectifier K+ channels, most likely from the inside of the membrane, in a way consistent with an open-channel block mechanism
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