Spatially compartmentalized phase regulation of a Ca2+-cAMP-PKA oscillatory circuit

Signaling networks are spatiotemporally organized in order to sense diverse inputs, process information, and carry out specific cellular tasks. In pancreatic β cells, Ca²⁺, cyclic adenosine monophosphate (cAMP), and Protein Kinase A (PKA) exist in an oscillatory circuit characterized by a high degree of feedback, which allows for specific signaling controls based on the oscillation frequencies. Here, we describe a novel mode of regulation within this circuit involving a spatial dependence of the relative phase between cAMP, PKA, and Ca²⁺. We show that nanodomain clustering of Ca²⁺-sensitive adenylyl cyclases drives oscillations of local cAMP levels to be precisely in-phase with Ca²⁺ oscillations, whereas Ca²⁺-sensitive phosphodiesterases maintain out-of-phase oscillations outside of the nanodomain, representing a striking example and novel mechanism of cAMP compartmentation. Disruption of this precise in-phase relationship perturbs Ca²⁺ oscillations, suggesting that the relative phase within an oscillatory circuit can encode specific functional information. This example of a signaling nanodomain utilized for localized tuning of an oscillatory circuit has broad implications for the spatiotemporal regulation of signaling networks.