Amplification of calcium-induced gene transcription by nitric oxide in neuronal cells

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 neurotransmitter in the central and peripheral nervous systems^1-5. 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 ^6-10. 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.