Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein.
In addition to mediating sexual maturation and reproduction through stimulation of classical intracellular receptors that bind DNA and regulate gene expression, estradiol is also thought to influence various brain functions by acting on receptors localized to the neuronal membrane surface. Many intracellular signaling pathways and modulatory proteins are affected by estradiol via this unconventional route, including regulation of the transcription factor cAMP response element-binding protein (CREB). However, the mechanisms by which estradiol acts at the membrane surface are poorly understood. Because both estradiol and CREB have been implicated in regulating learning and memory, we characterized the effects of estradiol on this transcription factor in cultured rat hippocampal neurons. Within minutes of administration, estradiol triggered mitogen-activated protein kinase (MAPK)-dependent CREB phosphorylation in unstimulated neurons. Furthermore, after brief depolarization, estradiol attenuated L-type calcium channel-mediated CREB phosphorylation. Thus, estradiol exhibited both positive and negative influences on CREB activity. These effects of estradiol were sex specific and traced to membrane-localized estrogen receptors that stimulated group I and II metabotropic glutamate receptor (mGluR) signaling. Activation of estrogen receptor alpha (ERalpha) led to mGluR1a signaling, triggering CREB phosphorylation through phospholipase C regulation of MAPK. In addition, estradiol stimulation of ERalpha or ERbeta triggered mGluR2/3 signaling, decreasing L-type calcium channel-mediated CREB phosphorylation. These results not only characterize estradiol regulation of CREB but also provide two putative signaling mechanisms that may account for many of the unexplained observations regarding the influence of estradiol on nervous system function.
Boulware
Marissa I
MI
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Weick
Jason P
JP
Becklund
Bryan R
BR
Kuo
Sidney P
SP
Groth
Rachel D
RD
Mermelstein
Paul G
PG
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism* / Q000502:physiology*; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C104077:metabotropic glutamate receptor type 1; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D011493:Protein Kinase C; D010738:Type C Phospholipases; D009543:Nifedipine; D011188:Potassium