RT Journal Article SR Electronic T1 Spatially compartmentalized phase regulation of a Ca2+-cAMP-PKA oscillatory circuit JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.01.10.902312 DO 10.1101/2020.01.10.902312 A1 Tenner, Brian A1 Getz, Michael A1 Ross, Brian A1 Ohadi, Donya A1 Bohrer, Christopher H. A1 Greenwald, Eric A1 Mehta, Sohum A1 Xiao, Jie A1 Rangamani, Padmini A1 Zhang, Jin YR 2020 UL http://biorxiv.org/content/early/2020/01/11/2020.01.10.902312.abstract AB 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.