Ca2+ and cAMP are widely used in concert by neurons to relay signals from the synapse to the nucleus, where synaptic activity modulates gene expression required for synaptic plasticity. Neurons utilize different transcriptional regulators to integrate information encoded in the spatiotemporal dynamics and magnitude of Ca2+ and cAMP signals, including some that are Ca2+-responsive, some that are cAMP-responsive and some that detect coincident Ca2+ and CAMP signals. Because Ca2+ and cAMP can influence each other's amplitude and spatiotemporal characteristics, we investigated how cAMP acts to regulate gene expression when increases in intracellular Ca2+ are buffered. We show here that cAMP-mobilizing stimuli are unable to induce expression of the immediate early gene c-fos in hippocampal neurons in the presence of the intracellular Ca2+ buffer BAPTA-AM. Expression of enzymes that attenuate intracellular IP3 levels also inhibited cAMP-dependent c-fos induction. Synaptic activity induces c-fos transcription through two cis regulatory DNA elements - the CRE and the SRE. We show here that in response to cAMP both CRE-mediated and SRE-mediated induction of a luciferase reporter gene is attenuated by IP3 metabolizing enzymes. Furthermore, cAMP-induced nuclear translocation of the CREB coactivator TORC1 was inhibited by depletion of intracellular Ca2+ stores. Our data indicate that Ca2+ release from IP3-sensitive pools is required for cAMP-induced transcription in hippocampal neurons. (c) 2012 Elsevier Inc. All rights reserved.