Tiziana Ruggiero (238561) & Francesca Bar (239273)
●Estradiol binds to nuclear receptors that act as ligand-activated transcription factors.
●Estradiol also activates extranuclear membrane receptors that stimulate intracellular signaling pathways through interaction with G proteins.
Nuclear ER
In neurons rapid actions of estradiol activate transcriptionally important signaling cascades and modulate ion channels.
● estrogen attenuates activated L-type voltage-gated Ca2+ channels,
● decreases glutamate-induced rise in intracellular calcium concentration ([Ca2+]i),
● uncouples opioid receptors from intracellular signaling cascades,
● modulates inositol-1,4,5,- trisphosphate (IP3) signaling and the release of [Ca2+]i stores.
Astrocytes express estrogen receptors (ER) and may mediate a number of estradiol-induced effects in the brain, for example, astrocyte ERs have been implicated in estrogen action on synaptic plasticity and neural repair.
Membrane ER
In addition to the transcriptional effects of estradiol via nuclear ERs, estradiol may rapidly activate cells by increasing cytoplasmic [Ca2+]i levels. Rapid effects of estrogen may be mediated by membrane ERs that activate the phospholipase C (PLC) pathway to increase [Ca2+]i flux.
ERα and ERβ proteins are associated with the plasma membrane and can be activated to modulate [Ca2+]i.
The membrane associated ERs appear to be G protein-coupled and the membrane ERα and Erβ in astrocytes activates a PLC signaling cascade that generates IP3. The IP3 binds to a receptor mediating the release of Ca2+ from smooth endoplasmic reticulum stores. So, estradiol produces a rapid stereospecific rise in [Ca2+]i from intracellular stores upon stimulation of the PLC/IP3 cascade, which is the first physiological cellular response that bring to a calcium-dependent protein kinase activation.
Astrocytes may regulate neurons by integrating synaptic signals and providing feedback responses based on variations in [Ca2+]i .
As in luteal cells, estradiol dramatically increases [Ca2+]i and facilitates the synthesis of progesterone; one interesting estrogen-astrocyte interaction is the synthesis of the neurosteroid in hypothalamus. The source of this estradiol-induced progesterone synthesis is astrocytic.
Although estradiol can elicit a release of Ca2+ through the formation of IP3 in neurons, granulose cells, and astrocytes, the predominant effect of estradiol in neurons has been to inhibit L-type voltage-gated Ca2+ channels. This has been demonstrated in neostriatal, hippocampal, and dorsal root ganglia neurons.
In neurons, estradiol did not activate [Ca2+]i directly, but rather, it attenuated the induced [Ca2+]i flux. Several different stimuli were used including ATP and glutamate.
The pharmacology of the astrocytic ER and the neuronal ER that mediate rapid [Ca2+]i transients were similar; the receptors were stereospecific. In neurons, however, the [Ca2+]i flux is dependent on extracellular Ca2+, but in astrocytes, estradiol stimulated the release of [Ca2+]i.
Reports
Functional significance of the rapid regulation of brain estrogens action: Where do the estrogens come from?
