Modulation of alphaCaMKII signaling by rapid ERalpha action.
The estrogen receptor (ER) subtypes, ERalpha and ERbeta, modulate numerous signaling cascades in the brain to result in a variety of cell fates including neuronal differentiation. We report here that 17beta-estradiol (E2) rapidly stimulates the autophosphorylation of alpha-Ca(2+)/calmodulin-dependent kinase II (alphaCaMKII) in immortalized NLT GnRH neurons, primary hippocampal neurons, and Cos7 cells co-transfected with ERalpha and alphaCaMKII. The E2-induced alphaCaMKII autophosphorylation is ERalpha- and Ca(2+)/calmodulin (CaM)-dependent. Interestingly, the hormone-dependent association of ERalpha with alphaCaMKII attenuates the positive effect of E2 on alphaCaMKII autophosphorylation, suggesting that ERalpha plays a complex role in modulating alphaCaMKII activity and may function to fine-tune alphaCaMKII-triggered signaling events. However, it appears as though the activating signal of E2 dominates the negative effect of ER since there is a clear, positive downstream response to E2-activated alphaCaMKII; pharmacological inhibitors and RNAi technology show that targets of ERalpha-mediated alphaCaMKII signaling include extracellular signal-regulated kinase 1/2 (ERK1/2), cAMP response element-binding protein (CREB), and microtubule associated protein 2 (MAP2). These findings suggest a novel model for the modulation of alphaCaMKII signaling by ERalpha, which provides a molecular link as to how E2 might influence brain function.
O'Neill
Erin E
EE
The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Blewett
Alexis R
AR
Loria
Paula M
PM
Greene
Geoffrey L
GL
D000818:Animals; D001345:Autoradiography; D002118:Calcium / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014162:Transfection / Q000379:methods
D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D004958:Estradiol; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D002118:Calcium