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Membrane estrogen receptor-alpha interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats.

ABSTRACT: In rats, female sexual behavior is regulated by a well defined limbic-hypothalamic circuit that integrates sensory and hormonal information. Estradiol activation of this circuit results in mu-opioid receptor (MOR) internalization in the medial preoptic nucleus, an important step for full expression of sexual receptivity. Estradiol acts through both membrane and intracellular receptors to influence neuronal activity and behavior, yet the mechanism(s) and physiological significance of estradiol-mediated membrane responses in vivo have remained elusive. Recent in vitro evidence found that stimulation of membrane-associated estrogen receptor-alpha (ER alpha) led to activation of metabotropic glutamate receptor 1a (mGluR1a). Furthermore, mGluR1a signaling was responsible for the observed downstream effects of estradiol. Here we present data that show that ER alpha and mGluR1a directly interact to mediate a rapid estradiol-induced activation of MOR in the medial preoptic nucleus, leading to female sexual receptivity. In addition, blockade of mGluR1a in the arcuate nucleus of the hypothalamus resulted in a significant attenuation of estradiol-induced MOR internalization, leading to diminished female sexual behavior. These results link membrane-initiated estradiol actions to neural events modulating behavior, demonstrating the physiological importance of ER alpha-to-mGluR1a signaling.

SUBMITTER: Dewing P

PROVIDER: S-EPMC2904398 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

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Membrane estrogen receptor-alpha interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats.

Dewing Phoebe P Boulware Marissa I MI Sinchak Kevin K Christensen Amy A Mermelstein Paul G PG Micevych Paul P

The Journal of neuroscience : the official journal of the Society for Neuroscience 20070801 35

In rats, female sexual behavior is regulated by a well defined limbic-hypothalamic circuit that integrates sensory and hormonal information. Estradiol activation of this circuit results in mu-opioid receptor (MOR) internalization in the medial preoptic nucleus, an important step for full expression of sexual receptivity. Estradiol acts through both membrane and intracellular receptors to influence neuronal activity and behavior, yet the mechanism(s) and physiological significance of estradiol-me ...[more]

PMID: 17728443

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Project description:In addition to the transcriptional activity of their liganded nuclear receptors, estrogens, such as estradiol (E2), modulate cell functions, and consequently physiology and behavior, within minutes through membrane-initiated events. The membrane-associated receptors (mERs) underlying the acute effects of estrogens on behavior have mostly been documented in females where active estrogens are thought to be of ovarian origin. We determined here, by acute intracerebroventricular injections of specific agonists and antagonists, the type(s) of mERs that modulate rapid effects of brain-derived estrogens on sexual motivation in male Japanese quail. Brain aromatase blockade acutely inhibited sexual motivation. Diarylpropionitrile (DPN), an estrogen receptor ? (ER?)-specific agonist, and to a lesser extent 17?-estradiol, possibly acting through ER-X, prevented this effect. In contrast, drugs targeting ER? (PPT and MPP), GPR30 (G1 and G15), and the Gq-mER (STX) did not affect sexual motivation. The mGluR1a antagonist LY367385 significantly inhibited sexual motivation but mGluR2/3 and mGluR5 antagonists were ineffective. LY367385 also blocked the behavioral restoration induced by E2 or DPN, providing functional evidence that ER? interacts with metabotropic glutamate receptor 1a (mGluR1a) signaling to acutely regulate male sexual motivation. Together these results show that ER? plays a key role in sexual behavior regulation and the recently uncovered cooperation between mERs and mGluRs is functional in males where it mediates the acute effects of estrogens produced centrally in response to social stimuli. The presence of an ER-mGluR interaction in birds suggests that this mechanism emerged relatively early in vertebrate history and is well conserved. Significance statement: The membrane-associated receptors underlying the acute effects of estrogens on behavior have mostly been documented in females, where active estrogens are thought to be of ovarian origin. Using acute intracerebroventricular injections of specific agonists and antagonists following blockade of brain aromatase, we show here that brain-derived estrogens acutely facilitate male sexual motivation through the activation of estrogen receptor ? interacting with the metabotropic glutamate receptor 1a. This behavioral effect occurring within minutes provides a mechanistic explanation of how an estrogen receptor not intrinsically coupled to intracellular effectors can signal from the membrane to govern behavior in a very rapid fashion. It suggests that different subtypes of estrogen receptors could regulate the motivation versus performance aspects of behavior.

Dataset Information

Membrane estrogen receptor-alpha interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats.

Publications

Membrane estrogen receptor-alpha interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats.

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