Nitric oxide (NO) is a short-lived, highly reactive gas, which has been identified as a mediator in vasodilation, an active agent in macrophage cytotoxicity and neurotoxicity, and a neuro-transmitter in the central and peripheral nervous systems. Production of NO by neurons is critical for facilitated synaptic transmission in models of synaptic plasticity such as long-term potentiation and long-term depression, suggesting a role for NO as a retrograde messenger that could complete a hypothetical feedback loop by strengthening the connection between postsynaptic and presynaptic cells. We report here that although alone NO has no evident effect on transcription, it can act as an amplifier of calcium signals in neuronal cells. NO and Ca2+ action have to coincide in time for amplification to occur. Experiments with a series of simplified reporter genes in combination with specific recombinant protein kinase inhibitors suggest that induction of gene activity following NO-amplified calcium action involves protein kinase A-dependent activation of the transcription factor CREB.