Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways.
Calcium ions (Ca2+) act as an intracellular second messenger and can enter neurons through various ion channels. Influx of Ca2+ through distinct types of Ca2+ channels may differentially activate biochemical processes. N-Methyl-D-aspartate (NMDA) receptors and L-type Ca2+ channels, two major sites of Ca2+ entry into hippocampal neurons, were found to transmit signals to the nucleus and regulated gene transcription through two distinct Ca2+ signaling pathways. Activation of the multifunctional Ca(2+)-calmodulin-dependent protein kinase (CaM kinase) was evoked by stimulation of either NMDA receptors or L-type Ca2+ channels; however, activation of CaM kinase appeared to be critical only for propagating the L-type Ca2+ channel signal to the nucleus. Also, the NMDA receptor and L-type Ca2+ channel pathways activated transcription by means of different cis-acting regulatory elements in the c-fos promoter. These results indicate that Ca2+, depending on its mode of entry into neurons, can activate two distinct signaling pathways. Differential signal processing may provide a mechanism by which Ca2+ controls diverse cellular functions.
Bading
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Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.
Ginty
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DD
Greenberg
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ME
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D016762:Genes, fos; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D006624:Hippocampus / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015290:Second Messenger Systems; D026362:Serum Response Factor; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection
D015220:Calcium Channels; D004268:DNA-Binding Proteins; D005971:Glutamates; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D026362:Serum Response Factor; D014157:Transcription Factors; D018698:Glutamic Acid; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium