Dual action of estrogen on glutamate-induced calcium signaling: mechanisms requiring interaction between estrogen receptors and src/mitogen activated protein kinase pathway.
Conjugated equine estrogens (CEE) is the most widely prescribed pharmaceutical estrogen replacement therapy (ERT) for postmenopausal women in the United States and is the ERT of the Women's Health Initiative. Previous studies from our laboratory have demonstrated that CEE exerts neurotrophic and neuroprotective effects in neurons involved in learning and memory, and which are affected in Alzheimer's disease. The present work demonstrates that CEE potentiated the rise in intracellular calcium ([Ca(2+)](i)) following exposure to physiological concentrations of glutamate. In contrast, the reverse effect occurred in the presence of excitotoxic levels of glutamate exposure, where CEE attenuated the rise in [Ca(2+)](i). Potentiation of the glutamate response was mediated by the NMDA receptor, as the NMDA receptor antagonist MK-801 blocked the CEE-induced potentiation, whereas the L-type calcium channel blocker nifedipine did not. Further, the CEE-potentiated glutamate response was mediated by a src tyrosine kinase, as the tyrosine kinase inhibitor PP2 blocked the potentiation induced by CEE and neurons treated with CEE displayed increased phosphorylated tyrosine. The inhibition by CEE of [Ca(2+)](i) rise in the presence of excitotoxic levels of glutamate was mediated by mitogen activated protein kinase (MAPK), as the protective effect of CEE was blocked by inhibiting MAPK activation with PD98059. These data provide potential mechanisms to explain the cognitive enhancing and neuroprotective effects exerted by ERT.
Nilsen
Jon
J
Department of Molecular Pharmacology and Toxicology, Pharmaceutical Sciences Center, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089, USA.
Chen
Shuhua
S
Brinton
Roberta Diaz
RD
D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005260:Female; D005470:Fluorometry; D018698:Glutamic Acid / Q000494:pharmacology*; D006736:Horses; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000187:drug effects; D008856:Microscopy, Fluorescence; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D004966:Estrogens, Conjugated (USP); D018690:Excitatory Amino Acid Agonists; D011960:Receptors, Estrogen; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D019061:src-Family Kinases