Decoding Ca²⁺ signals through cAMP

Transient changes in intracellular Ca²⁺ concentrations drive many biological processes, from gene transcription to growth cone turning. Ca²⁺ elevations can initiate cAMP oscillations, but new results suggest that only specific patterns of Ca²⁺ have this ability. Yuliya Gorbunova (University of Medicine & Dentistry of New Jersey, Piscataway, NJ) and Nicholas Spitzer (University of California, San Diego, CA) anticipate that their results may shift the focus in the field from Ca²⁺ spike frequency to spike timing and pattern.

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. ▪

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