Membrane Estrogen Receptor-α 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 -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-␣ (ER␣) 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␣ 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␣-to-mGluR1a signaling.

Membrane-initiated estrogen signaling in hypothalamic neurons

“…The type of interaction, however, is currently unknown, but potentially could be similar to that described for mER and 5HT 2C receptors which have diverse but convergent signaling pathways in arcuate neurons (Qiu et al, 2007). A similar scenario has been hypothesized for the rapid E2-induced activation of μ-opioid receptors in the medial preoptic area associated with female sex behavior (Dewing et al, 2007). Based on responses to the ER agonists, propylpyrazoletriol (PPT) and diarylpropionitrile (DPN), which are selective for ERα and ERβ, respectively, and transfection studies with mutant ERα (Harrington et al, 2003, Lund et al, 2006, the membrane-localized receptors in the hippocampus are hypothesized to be ERβ and ERβ (Boulware et al, 2005.…”

“…However, it is now widely accepted that some of the actions of estrogen are quite rapid and cannot be attributed to the classical nuclear-initiated steroid signaling of ERα or ERβ. One view is that both nuclear and plasma membrane-associated ERs might be products of the same genes (Razandi et al, 1999, Boulware et al, 2005, Pedram et al, 2006, Szegõ et al, 2006, Dewing et al, 2007. This belief stems primarily from the fact that many of the rapid effects of E2 can be induced by selective ERα or ERβ ligands, antagonized by the ER antagonist, ICI 182,780, or are lost in animals bearing mutations in ERα and/or ERβ genes (Couse and Korach, 1999, Singer et al, 1999, Dubal et al, 2001, Wade et al, 2001, Abraham et al, 2003, Boulware et al, 2005.…”

Caveolin proteins and estrogen signaling in the brain

“…Thus far, it has been determined that caveolin proteins functionally link estrogen receptors with mGluRs in striatal neurons [92]; other regions await verification. Through influencing these additional regions, rapid estrogen receptor signaling has been suggested to modulate multiple cellular processes, such as motor control and drug addiction [12,[95][96][97], sexual receptivity [91], the control of the estrous cycle [98], and nociception [14,99]. Furthermore, while we and others hypothesize GPCRs to act as intermediaries between estrogen receptors and G proteins, others have postulated that estrogen receptors directly activate the G proteins [100].…”

“…mGluRs appear required for membrane estrogen receptor signaling in several other systems including neurons of the arcuate nucleus [91], striatal neurons [92], dorsal root ganglia [93] and hypothalamic astrocytes [94]. Thus far, it has been determined that caveolin proteins functionally link estrogen receptors with mGluRs in striatal neurons [92]; other regions await verification.…”

mGlu receptors in endocrine organs

“…50 Estradiol activation of mGlu receptors is independent of glutamatergic transmission. [49][50][51] Instead, Dewing et al (2007) 52 proposed a transactivation mechanism by which ERs activate mGlu receptors following estradiol stimulation via direct protein-protein interaction. Caveolin proteins were found essential for various membrane ERα responses since they compartmentalize the different ERs with mGlu receptors into functional signaling microdomains.…”