DISTINCT FUNCTIONS OF NUCLEAR AND CYTOPLASMIC CALCIUM IN THE CONTROL OF GENE-EXPRESSION

Calcium entry into neuronal cells through voltage or ligand-gated ion channels triggers neuronal affinity-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 o f nuclear calcium(6-9), but the functional significance of such spatia lly distinct calcium signals is unknown. Here we show that gene expres sion is differentially controlled by nuclear and cytoplasmic calcium s ignals which enable a single second messenger to generate diverse tran scriptional responses, We used nuclear microinjection of a nondiffusib le 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 concentr ation control calcium-activated gene expression mediated by the cyclic -AMP-response element (CRE), and demonstrated that the CRE-binding pro tein CREB can function as a nuclear calcium-responsive transcription f actor. A second signalling pathway, activating transcription through t he serum-response element (SRE), is triggered by a rise in cytoplasmic calcium and does not require an increase in nuclear calcium.