Dynamic interactions of cyclic AMP transients and spontaneous Ca2+ spikes

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Abstract
Transient increases of intracellular Ca2+ drive many cellular processes, ranging from membrane channel kinetics to transcriptional regulation1,2,3,4,5, and links of Ca2+ to other second messengers should activate signalling networks6,7,8,9,10,11. 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 Ca2+ oscillations. Blocking the production of these cAMP transients decreases the intrinsic frequency of spontaneous Ca2+ spikes, whereas inducing cAMP increases causes spike frequency to increase. Transients of cAMP in turn are absent when Ca2+ spikes are blocked, and are generated only in response to specific patterns of stimulated spikes that mimic endogenous Ca2+ kinetics. We present a mathematical model of Ca2+–cAMP reciprocity that generates the slow cAMP oscillations and reproduces the dynamics of Ca2+–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 Ca2+ 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.