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First published online 14 February 2006
doi: 10.1242/jcs.02812

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Ca²⁺ stimulation of adenylyl cyclase generates dynamic oscillations in cyclic AMP

Department of Pharmacology, Tennis Court Road, University of Cambridge, CB2 1PD, UK

^* Author for correspondence (e-mail: dmfc2{at}cam.ac.uk)

Accepted 15 November 2005

The spatial and temporal complexity of Ca²⁺ signalling is central to the regulation of a diverse range of cellular processes. The decoding of dynamic Ca²⁺ signals is, in part, mediated by the ability of Ca²⁺ to regulate other second messengers, including cyclic AMP (cAMP). A number of kinetic models (including our own) predict that interdependent Ca²⁺ and cAMP oscillations can be generated. A previous study in Xenopus neurons illustrated prolonged, low-frequency cAMP oscillations during bursts of Ca²⁺ transients. However, the detection of more dynamic Ca²⁺ driven changes in cAMP has, until recently, been limited by the availability of suitable cAMP probes with high temporal resolution. We have used a newly developed FRET-based cAMP indicator comprised of the cAMP binding domain of Epac-1 to examine interplay between Ca²⁺ and cAMP dynamics. This probe was recently used in excitable cells to reveal an inverse relationship between cAMP and Ca²⁺ oscillations as a consequence of Ca²⁺-dependent activation of phosphodiesterase 1 (PDE1). Here, we have used human embryonic kidney (HEK293) cells expressing the type 8 adenylyl cyclase (AC8) to examine whether dynamic Ca²⁺ changes can mediate phasic cAMP oscillations as a consequence of Ca²⁺-stimulated AC activity. During artificial or agonist-induced Ca²⁺ oscillations we detected fast, periodic changes in cAMP that depended upon Ca²⁺ stimulation of AC8 with subsequent PKA-mediated phosphodiesterase 4 (PDE4) activity. Carbachol (10 µM) evoked cAMP transients with a peak frequency of 3 minute^-1, demonstrating phasic oscillations in cAMP and Ca²⁺ in response to physiological stimuli. Furthermore, by imposing a range of Ca²⁺-oscillation frequencies, we demonstrate that AC8 acts as a low-pass filter for high-frequency Ca²⁺ events, enhancing the regulatory options available to this signalling pathway.

Key words: Calcium, cAMP, Oscillation, Adenylyl cyclase, Phosphodiesterase

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