Calcium Flux in Neuroblastoma Cells Is a Coupling Mechanism between Non-Genomic and Genomic Modes of Estrogens

Abstract

Estrogens have been demonstrated to rapidly modulate calcium levels in a variety of cell types. However, the significance of estrogen-mediated calcium flux in neuronal cells is largely unknown. The relative importance of intra- and extracellular sources of calcium in estrogenic effects on neurons is also not well understood. Previously, we have demonstrated that membrane-limited estrogens, such as E-BSA given before an administration of a 2-hour pulse of 17β-estradiol (E₂), can potentiate the transcription mediated by E₂ from a consensus estrogen response element (ERE)-driven reporter gene. Inhibitors to signal transduction cascades given along with E-BSA or E₂ demonstrated that calcium flux is important for E-BSA-mediated potentiation of transcription in a transiently transfected neuroblastoma cell line. In this report, we have used inhibitors to different voltage-gated calcium channels (VGCCs) and to intracellular store receptors along with E-BSA in the first pulse or with E₂ in the second pulse to investigate the relative importance of these channels to estrogen-mediated transcription. Neither L- nor P-type VGCCs seem to play a role in estrogen action in these cells; while N-type VGCCs are important in both the non-genomic and genomic modes of estrogen action. Specific inhibitors also showed that the ryanodine receptor and the inositol trisphosphate receptor are important to E-BSA-mediated transcriptional potentiation. This report provides evidence that while intracellular stores of calcium are required to couple non-genomic actions of estrogen initiated at the membrane to transcription in the nucleus, extracellular sources of calcium are also important in both non-genomic and genomic actions of estrogens.

Protein kinase C modulates transcriptional activation by the juvenile hormone receptor methoprene-tolerant

“…The nongenomic steroid activity typically involves the rapid activation of second messenger systems and activation of PKC, PI3K and mitogen-activated protein kinase (Hammes and Levin, 2007; Pietras and Szego, 1975; Szego and Davis, 1967). This rapid action initiates at the cell surface and can be readily induced by cell-impermeable hormone conjugates (Zhao et al, 2005; Zheng et al, 1996). …”

Estrogen: A master regulator of bioenergetic systems in the brain and body

“…These membrane sites of ER action activate both the Src/PI3K and Ras/Raf/MEKK/ERK signaling pathways, leading to activation of CREB, and they have been identified as required for E 2 -inducible neuroprotection (Levin, 2001; Mannella and Brinton, 2006; Zhao et al, 2005). G protein-coupled receptors that associate with estrogen, such as G-protein coupled estrogen receptor 1 (GPER1; also called GPR30) (HUGO Gene Nomenclature Committee, NCBI), have also been identified (Maggiolini and Picard, 2010).…”

Estrogen-Mediated Protection in Myocardial Ischemia-Reperfusion Injury

“…It is apparent that the receptor also modulates the activity of intracellular second messengers, membraneassociated receptors, and signaling complexes, which may enhance the classic activity of the ER. Non-genomic actions of E2 have been described in several model systems and include changes in Ca 2+ flux [124], mitogen activated protein kinase (MAPK) activation [57], and activation of the PI3K-AKT pathway [83]. These effects are believed to be mediated by estrogen receptors, possibly the classical ER, located in or close to the plasma membrane [20].…”