Spatially Compartmentalized Phase Regulation in the Ca2+-cAMP-PKA-Oscillatory Circuit

Abstract

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, and this circuit is instrumental in mediating and potentiating pulsatile insulin secretion. 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 within the membrane nanodomain to be precisely in-phase with Ca2+ oscillations, whereas Ca2+-sensitive phosphodiesterases maintains out-of-phase oscillations within the general plasma membrane, providing 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 coordination of many biological networks.