An oscillatory circuit that interlinks Ca2+, cAMP and PKA to integrate multiple input signals and coordinate key signaling activities via frequency modulation, thereby regulating complex functions in a context-dependent manner.
(A) A FRET-based calcineurin activity reporter (CaNAR), which consists of a calcineurin substrate sandwiched between CFP and YFP. (B) Dual imaging of Ca2+ (red) and calcineurin activity (black) revealed integrative cytosolic calcineurin activity, contrasted by an oscillatory activity pattern on the ER, in response to Ca2+ oscillations. (C) These data are consistent with a model in which free Ca2+/CaM is less abundant near the ER surface, thereby leading to weaker calcineurin activation and calcineurin activity oscillations in this compartment.
In the classical model of cAMP/PKA signaling, nuclear PKA signaling is thought to result from the gradual diffusion of activated PKA from the cytosol into the nucleus. However, our work indicates that the nucleus contains a resident pool of PKA holoenzyme, whose activity is tightly regulated through the formation of an AKAP-dependent signaling microdomain that contains both PKA holoenzyme and PDEs.
