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Optical Mapping of cAMP Signaling at the Nanometer Scale

Bock, Andreas; Annibale, Paolo; Konrad, Charlotte; Hannawacker, Annette; Anton, Selma E.; Maiellaro, Isabella; Zabel, Ulrike; Sivaramakrishnan, Sivaraj; Falcke, Martin; Lohse, Martin J.

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Andreas Bock

Paolo Annibale

Charlotte Konrad

Annette Hannawacker

Selma E. Anton

Ulrike Zabel

Sivaraj Sivaramakrishnan

Martin Falcke

Martin J. Lohse


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.


Bock, A., Annibale, P., Konrad, C., Hannawacker, A., Anton, S. E., Maiellaro, I., …Lohse, M. J. (2020). Optical Mapping of cAMP Signaling at the Nanometer Scale. Cell, 182(6), 1519-1530.e17.

Journal Article Type Article
Acceptance Date Jul 25, 2020
Online Publication Date Aug 25, 2020
Publication Date Sep 17, 2020
Deposit Date Sep 1, 2020
Publicly Available Date Aug 26, 2021
Journal Cell
Print ISSN 0092-8674
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 182
Issue 6
Pages 1519-1530.e17
Keywords General Biochemistry, Genetics and Molecular Biology
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