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Trends Pharmacol Sci. 2018 Feb;39(2):209-222. doi: 10.1016/j.tips.2017.11.006. Epub 2017 Dec 27.

cAMP: From Long-Range Second Messenger to Nanodomain Signalling.

Author information

1
Department of Molecular Pharmacology, University of Groningen, The Netherlands; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
2
Department of Molecular Pharmacology, University of Groningen, The Netherlands; Groningen Research Institute for Asthma and COPD, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
3
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. Electronic address: manuela.zaccolo@dpag.ox.ac.uk.

Abstract

How cAMP generates hormone-specific effects has been debated for many decades. Fluorescence resonance energy transfer (FRET)-based sensors for cAMP allow real-time imaging of the second messenger in intact cells with high spatiotemporal resolution. This technology has made it possible to directly demonstrate that cAMP signals are compartmentalised. The details of such signal compartmentalisation are still being uncovered, and recent findings reveal a previously unsuspected submicroscopic heterogeneity of intracellular cAMP. A model is emerging where specificity depends on compartmentalisation and where the physiologically relevant signals are those that occur within confined nanodomains, rather than bulk changes in cytosolic cAMP. These findings subvert the classical notion of cAMP signalling and provide a new framework for the development of targeted therapeutic approaches.

KEYWORDS:

FRET imaging; G protein coupled receptors; cAMP; compartmentalisation; phosphodiesterases; protein kinase A

PMID:
29289379
DOI:
10.1016/j.tips.2017.11.006
[Indexed for MEDLINE]

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