Membrane estrogen signaling in female reproduction and motivation

Abstract

Estrogen receptors were initially identified in the uterus, and later throughout the brain and body as intracellular, ligand-regulated transcription factors that affect genomic change upon ligand binding. However, rapid estrogen receptor signaling initiated outside of the nucleus was also known to occur via mechanisms that were less clear. Recent studies indicate that these traditional receptors, estrogen receptor-α and estrogen receptor-β, can also be trafficked to act at the surface membrane. Signaling cascades from these membrane-bound estrogen receptors (mERs) not only rapidly effect cellular excitability, but can and do ultimately affect gene expression, as seen through the phosphorylation of CREB. A principal mechanism of neuronal mER action is through glutamate-independent transactivation of metabotropic glutamate receptors (mGluRs), which elicits multiple signaling outcomes. The interaction of mERs with mGluRs has been shown to be important in many diverse functions in females, including, but not limited to, reproduction and motivation. Here we review membrane-initiated estrogen receptor signaling in females, with a focus on the interactions between these mERs and mGluRs.

Keywords: estrogen; estrogen receptor signaling; estrogen receptors; membrane estrogen receptors; metabotropic glutamate (mGlu) receptors.

Figure 1

mER transactivation of group I and group II mGluRs. 17β-Estradiol (17βE) binds to membrane-bound estrogen receptors (ER) to activate distinct signaling pathways via Group I (A) or Group II (B) mGluRs. (A) Membrane-ER interactions with Group I mGluRs, dependent on CAV1, activates G_q-mediated signaling through protein lipase C (PLC) and protein kinase C (PKC), subsequent activation of MEK, MAPK, and RSK, and ultimately the phosphorylation of CREB. PLC also activates IP3, which binds to the IP3 receptor (IP3R) to result in the release of intracellular calcium (Ca²⁺). (B) Membrane-ER activation of Group II mGluRs, dependent on CAV3, results in the G_i/o-mediated inhibition of adenylyl cyclase (AC), decreasing the activity (indicated by dashed lines) of protein kinase A (PKA). This results in reduced L-type calcium channel currents and L-type calcium channel-dependent CREB phosphorylation. CaM, Calmodulin; CaMKIV, calmodulin-dependent protein kinase IV; CAV, caveolin; IP3, inositol triphosphate; MEK, MAPK/ERK kinase; MAPK, mitogen-activated protein kinase; RSK, ribosomal S6 kinase. Figure adapted from (32).

Figure 2

Hypothalamic lordosis circuit. Estradiol acts on estrogen receptor-containing NPY neurons in the ARH, which further project to and activate ARH POMC/B-End neurons. These POMC neurons project to the MPN where the release of B-End activates and internalizes MORs. When these receptors are internalized, lordosis is attenuated. In the ARH, the interaction of mERα & mGluR1a is important for both the internalization of MOR and ultimately the display of lordosis. These MOR-containing neurons in the MPN project further to the ventrolateral (vl) part of the VMH, where signals from other circuits are integrated. Projections from the VMHvl reach lower brain regions which ultimately innervate the spinal motor neurons responsible for the production of the behavior. 3V, 3rd ventricle; OC, optic chiasm; ME, median eminence. Figure adapted from (66).