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

ELife
Brian TennerJin Zhang

Abstract

Signaling networks are spatiotemporally organized to sense diverse inputs, process information, and carry out specific cellular tasks. In β cells, Ca2+, cyclic adenosine monophosphate (cAMP), and Protein Kinase A (PKA) exist in an oscillatory circuit characterized by a high degree of feedback. Here, we describe a mode of regulation within this circuit involving a spatial dependence of the relative phase between cAMP, PKA, and Ca2+. We show that in mouse MIN6 β cells, nanodomain clustering of Ca2+-sensitive adenylyl cyclases (ACs) 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. Disruption of this precise phase relationship perturbs Ca2+ oscillations, suggesting the relative phase within an oscillatory circuit can encode specific functional information. This work unveils a novel mechanism of cAMP compartmentation utilized for localized tuning of an oscillatory circuit and has broad implications for the spatiotemporal regulation of signaling networks.

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Citations

Nov 18, 2020·ELife·Sascha M Kuhn, André Nadler
Jan 17, 2021·Molecular Cell·Stephen C ThornquistMichael A Crickmore
Feb 23, 2021·The Journal of Biological Chemistry·Veronica A CochraneShow-Ling Shyng
Aug 29, 2021·Bio Systems·Esperanza Mata-MartínezAlberto Darszon
Sep 14, 2021·Journal of the American Chemical Society·Wei LinJin Zhang

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Methods Mentioned

BETA
biosensor
biosensors
Fluorescence Recovery After Photobleaching
proximity ligation assay
proximity ligation
FRET

Software Mentioned

Graphpad Prism
Stochastic Optical Reconstruction Microscopy ( STORM
METAFLUOR
MATLAB scripts
custom
MATLAB
Java
Nikon Elements
CellProfiler
NIS Elements

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