Spatiotemporal Regulation of Signaling

Discovery of an oscillatory circuit in insulin-secreting β cells

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.

Oscillatory Circuit

Calcineurin signaling in MIN6 β cells

(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.

PKA cakcuneurin

Model of nuclear PKA microdomain

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.

PKA Domain