Estrogen-induced activation of extracellular signal-regulated kinase signaling triggers dendritic resident mRNA translation.
Activated extracellular signal-regulated kinase (ERK) signaling mediated plasticity-related gene transcription has been proposed for one possible mechanism by which 17β-estradiol (E2) enhances synaptic plasticity and memory. Because activated ERK also enhances plasticity-related mRNA translation in the dendrites of neurons, we sought to determine the effects of E2 on activation of ERK, phosphorylation of translation initiation factors, and dendritic mRNA translation in hippocampal neurons. Acute E2 application resulted in a rapid, transient increase in phosphorylation of translation initiation factors, ribosomal protein (S6) and eIF4E binding protein1 (4EBP1), in an activated ERK-dependent manner. Since phosphorylation of these translation factors enhance mRNA translation, we tested E2's effect on dendritic mRNA translation. Using a green fluorescent protein (GFP)-based dendritic mRNA translation reporter (reporter plasmid construct consisted of a GFP gene fused to the 3' untranslated region (UTR) from CAMKIIα, which contains dendritic resident mRNA targeting and mRNA translational regulatory elements) we showed that E2 treatment resulted in increased somatic and dendritic GFP mRNA translation in GFP-reporter transfected hippocampal neurons. Translation inhibitor anisomycin and ERK inhibitor U0126 blocked E2 effects. Taken together, our results provide a novel mechanism by which E2 may trigger local protein synthesis of α-CaMKII in the dendrites, which is necessary for modulation of synaptic plasticity.
Sarkar
S N
SN
Department of Pharmacology and Neuroscience, University of North Texas, Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
Smith
L T
LT
Logan
S M
SM
Simpkins
J W
JW
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000096:biosynthesis* / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction
D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D038601:Ribosomal Protein S6; D049452:Green Fluorescent Proteins; D004958:Estradiol; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases