PT  - JOURNAL ARTICLE
AU  - Tenner, Brian
AU  - Getz, Michael
AU  - Ross, Brian
AU  - Ohadi, Donya
AU  - Bohrer, Christopher H.
AU  - Greenwald, Eric
AU  - Mehta, Sohum
AU  - Xiao, Jie
AU  - Rangamani, Padmini
AU  - Zhang, Jin
TI  - Spatially compartmentalized phase regulation of a Ca<sup>2+</sup>-cAMP-PKA oscillatory circuit
AID  - 10.1101/2020.01.10.902312
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.10.902312
4099  - http://biorxiv.org/content/early/2020/01/11/2020.01.10.902312.short
4100  - http://biorxiv.org/content/early/2020/01/11/2020.01.10.902312.full
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.