Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression

• Published in: Nature (London) 1997-01, Vol.385 (6613), p.260-265
• Main Authors: Hardingham, Giles E, Chawla, Sangeeta, Johnson, Claire M, Bading, Hilmar
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Calcium; Calcium - physiology; Calcium Channel Agonists - pharmacology; Calcium channels; Cell Line; Cell Nucleus - physiology; Chelating Agents - pharmacology; Cyclic AMP Response Element-Binding Protein - metabolism; Cytoplasm - physiology; DNA-Binding Proteins - metabolism; Egtazic Acid - analogs & derivatives; Egtazic Acid - pharmacology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Genes; Genes, fos; Humanities and Social Sciences; Humans; letter; Mice; Molecular and cellular biology; Molecular genetics; multidisciplinary; Neurons; Nuclear Proteins - metabolism; Potassium Chloride - pharmacology; Pyrroles - pharmacology; Science; Science (multidisciplinary); Second Messenger Systems; Serum Response Factor; Transcription Factors - metabolism; Transcription, Genetic
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/385260a0

Calcium entry into neuronal cells through voltage or ligand-gated ion channels triggers neuronal activity-dependent gene expression critical for adaptive changes in the nervous system 1–5 . Cytoplasmic calcium transients are often accompanied by an increase in the concentration of nuclear calcium 6–9 , but the functional significance of such spatially distinct calcium signals is unknown. Here we show that gene expression is differentially controlled by nuclear and cytoplasmic calcium signals which enable a single second messenger to generate diverse transcriptional responses. We used nuclear microinjection of a non-diffusible calcium chelator to block increases in nuclear, but not cytoplasmic, calcium concentrations following activation of L-type voltage-gated calcium channels. We showed that increases in nuclear calcium concentration control calcium-activated gene expression mediated by the cyclic-AMP-response element (CRE), and demonstrated that the CRE-binding protein CREB can function as a nuclear calcium-responsive transcription factor. A second signalling pathway, activating transcription through the serum-response element (SRE), is triggered by a rise in cytoplasmic calcium and does not require an increase in nuclear calcium.