The two examined reciprocity in Ca2+/cAMP signaling in embryonic spinal neurons using fluorescent indicator dyes. In culture, increases in cAMP levels increased the frequency of Ca2+ spikes in neurons, whereas decreasing cAMP production had the reverse effect. Blocking Ca2+ spikes inhibited cAMP increases. Only specific patterns of induced Ca2+ transients caused cAMP transients—singlets of Ca2+ spikes were ineffective at producing cAMP oscillations, but triplets of Ca2+ spikes in rapid succession were effective. Spitzer predicts the resulting cAMP oscillations control transcriptional regulation of genes responsive to these frequencies of Ca2+ transients.
They then derived a mathematical model to characterize cAMP/Ca2+ reciprocity. “If cells are generating this activity naturally, it's probably important,” says Spitzer. The model will allow them to test certain predictions quickly and determine the interest of the results to pursue in biological experiments. For instance, the model predicts that coincident elevation of both cAMP and IP3 in a cell results in negative interaction between the messengers; only specific combinations of concentrations of the two produce Ca2+ and cAMP transients. Testing this hypothesis in cells may help reveal how neurons coordinate multiple signals to produce the appropriate result. ▪