Estradiol and intracellular Calcium concentration

Author: Francesca Bar
Date: 08/10/2007


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.

Functional significance of the rapid regulation of brain estrogens action: Where do the estrogens come from?

2012-02-20T15:42:18 - mefarete gurguri

Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase.
The endothelial nitric oxide synthase (eNOS), the expression of which is regulated by a range of transcriptional and post transcriptional mechanisms, generates nitric oxide (NO) in response to a number of stimuli. The physiologically most important determinants for the continuous generation of NO and thus the regulation of local blood flow are fluid shear stress and pulsatile stretch. Although eNOS activity is coupled to changes in endothelial cell Ca2+ levels, an increase in Ca2+ alone is not sufficient to affect enzyme activity because the binding of calmodulin (CaM) and the flow of electrons from the reductase to the oxygenase domain of the enzyme is dependent on protein phosphorylation and dephosphorylation. Two amino acids seem to be particularly important in regulating eNOS activity and these are a serine residue in the reductase domain (Ser1177) and a threonine residue (Thr495) located within the CaM-binding domain. Simultaneous alterations in the phosphorylation of Ser1177 and Thr495 in response to a variety of stimuli are regulated by a number of kinases and phosphatases that continuously associate with and dissociate from the eNOS signaling complex. eNOS associated proteins, such as caveolin, heat shock protein 90, eNOS interacting protein, and possibly also motor proteins provide the scaffold for the formation of the protein complex as well as its intracellular localization.
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