Estrogen stimulates postsynaptic density-95 rapid protein synthesis via the Akt/protein kinase B pathway.
Estrogens induce synaptogenesis in the CA1 region of the dorsal hippocampus during the estrous cycle of the female rat. Functional consequences of such estrogen-mediated synaptogenesis include cyclic changes in neurotransmission and memory. At the molecular level, estrogen stimulates the rapid activation of specific signal transduction pathways, and of particular interest is the activation of Akt (protein kinase B), a key signal transduction intermediate that initiates protein translation by alleviating the downstream translational repression of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Using a well established in vitro model system of differentiated NG108-15 neurons to investigate such rapid signaling effects of estrogen, we show that estrogen stimulates the phosphorylation of Akt, an indication of kinase activation, as well as the phosphorylation of 4E-BP1. In turn, the activation of these signaling intermediates suggests a non-genomic mechanism by which estrogen might likewise lead to protein translation of dendrite-localized mRNA transcripts in the hippocampus in vivo. We therefore considered the translation of the dendritic spine scaffolding protein postsynaptic density-95 (PSD-95). Although estrogen does not stimulate a rapid increase in PSD-95 mRNA levels in NG108-15 neurons, we show here that estrogen does however stimulate a rapid increase in PSD-95 new protein synthesis in vitro and that this new protein synthesis is Akt dependent. These results demonstrate an essential role for Akt in estrogen-stimulated dendritic spine protein expression, describe for the first time a signal transduction pathway in PSD-95 expression, and delineate a novel, molecular mechanism by which ovarian hormones might translationally regulate synaptogenesis via activating protein synthesis for dendritic function.
Akama
Keith T
KT
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York 10021-6399, USA.
McEwen
Bruce S
BS
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D003712:Dendrites / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004958:Estradiol / Q000494:pharmacology*; D039642:Eukaryotic Initiation Factors; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C501449:Dlg4 protein, rat; C499527:Eif4ebp1 protein, mouse; C499526:Eif4ebp1 protein, rat; D039642:Eukaryotic Initiation Factors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C033652:postsynaptic density proteins; D004958:Estradiol; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051528:Guanylate Kinases