Estradiol Activates Group I and II Metabotropic Glutamate Receptor Signaling, Leading to Opposing Influences on cAMP Response Element-Binding Protein

• Published in: The Journal of neuroscience 2005-05, Vol.25 (20), p.5066-5078
• Main Authors: Boulware, Marissa I, Weick, Jason P, Becklund, Bryan R, Kuo, Sidney P, Groth, Rachel D, Mermelstein, Paul G
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Blotting, Western - methods; Calcium Channel Blockers - pharmacology; Calcium Channels - metabolism; Cell Membrane - drug effects; Cells, Cultured; Cyclic AMP Response Element-Binding Protein - metabolism; Development/Plasticity/Repair; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Estradiol - pharmacology; Estrogen Antagonists - pharmacology; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Fluorescent Antibody Technique - methods; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Hippocampus - cytology; Humans; Inositol 1,4,5-Trisphosphate Receptors; Male; Microtubule-Associated Proteins - metabolism; Nifedipine - pharmacology; Phosphorylation - drug effects; Potassium - pharmacology; Protein Kinase C - metabolism; Pyramidal Cells - cytology; Pyramidal Cells - drug effects; Pyramidal Cells - physiology; Rats; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Metabotropic Glutamate - metabolism; Receptors, Metabotropic Glutamate - physiology; Sex Factors; Signal Transduction - drug effects; Tamoxifen - analogs & derivatives; Tamoxifen - pharmacology; Time Factors; Type C Phospholipases - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1427-05.2005

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.