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Optical mapping of cAMP signaling at the nanometer scale

Item Type:Article
Title:Optical mapping of cAMP signaling at the nanometer scale
Creators Name:Bock, A. and Annibale, P. and Konrad, C. and Hannawacker, A. and Anton, S.E. and Maiellaro, I. and Zabel, U. and Sivaramakrishnan, S. and Falcke, M. and Lohse, M.J.
Abstract:Cells relay a plethora of extracellular signals to specific cellular responses by using only a few second messengers, such as cAMP. To explain signaling specificity, cAMP-degrading phosphodiesterases (PDEs) have been suggested to confine cAMP to distinct cellular compartments. However, measured rates of fast cAMP diffusion and slow PDE activity render cAMP compartmentalization essentially impossible. Using fluorescence spectroscopy, we show that, contrary to earlier data, cAMP at physiological concentrations is predominantly bound to cAMP binding sites and, thus, immobile. Binding and unbinding results in largely reduced cAMP dynamics, which we term "buffered diffusion." With a large fraction of cAMP being buffered, PDEs can create nanometer-size domains of low cAMP concentrations. Using FRET-cAMP nanorulers, we directly map cAMP gradients at the nanoscale around PDE molecules and the areas of resulting downstream activation of cAMP-dependent protein kinase (PKA). Our study reveals that spatiotemporal cAMP signaling is under precise control of nanometer-size domains shaped by PDEs that gate activation of downstream effectors.
Keywords:Cyclic AMP, Compartmentation, Protein Kinase A4, Phosphodiesterase, Buffered Diffusion, Nanodomains, FRET Biosensors, Fluorescence Fluctuation Spectroscopy, G Protein-Coupled Receptors, Cell Signaling
Source:Cell
ISSN:0092-8674
Publisher:Cell Press
Volume:182
Number:6
Page Range:1519-1530
Date:17 September 2020
Official Publication:https://doi.org/10.1016/j.cell.2020.07.035
PubMed:View item in PubMed

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