Dynamic interactions of cyclic AMP transients and spontaneous Ca(2+) spikes

Transient increases of intracellular Ca(2+) drive many cellular processes, ranging from membrane channel kinetics to transcriptional regulation, and links of Ca(2+) to other second messengers should activate signalling networks. However, real-time kinetic interactions have been difficult to investigate. Here we report observations of spontaneous increases in concentration of cyclic AMP (cAMP) in embryonic spinal neurons, and their dynamic interactions with Ca(2+) oscillations. Blocking the production of these cAMP transients decreases the intrinsic frequency of spontaneous Ca(2+) spikes, whereas inducing cAMP increases causes spike frequency to increase. Transients of cAMP in turn are absent when Ca(2+) spikes are blocked, and are generated only in response to specific patterns of stimulated spikes that mimic endogenous Ca(2+) kinetics. We present a mathematical model of Ca(2+)-cAMP reciprocity that generates the slow cAMP oscillations and reproduces the dynamics of Ca(2+)-cAMP interactions observed experimentally. The model predicts that this module of coupled second messengers is tuned to optimize production of cAMP transients, and that simultaneous stimulation of Ca(2+) and cAMP systems produces distinct temporal patterns of oscillations of both messengers. Our findings may prove useful in the investigation of the regulation of gene expression by second-messenger transients.