FRET biosensor uncovers cAMP nano-domains at β-adrenergic targets that dictate precise tuning of cardiac contractility

Nicoletta C. Surdo, Marco Berrera, Andreas Koschinski, Marcella Brescia, Matias R. Machado, Carolyn Carr, Peter Wright, Julia Gorelik, Stefano Morotti, Eleonora Grandi, Donald M. Bers, Sergio Pantano and Manuela Zaccolo
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Nicoletta C. Surdo: Anatomy and Genetics, University of Oxford
Marco Berrera: Molecular Pharmacology Centre, Institute of Neuroscience and Psychology, University of Glasgow
Andreas Koschinski: Anatomy and Genetics, University of Oxford
Marcella Brescia: Anatomy and Genetics, University of Oxford
Matias R. Machado: Group of Biomolecular Simulations, Institute Pasteur de Montevideo
Carolyn Carr: Anatomy and Genetics, University of Oxford
Peter Wright: National Heart and Lung Institute, Imperial Centre for Translational and Experimental Medicine, Imperial College London
Julia Gorelik: National Heart and Lung Institute, Imperial Centre for Translational and Experimental Medicine, Imperial College London
Stefano Morotti: University of California Davis
Eleonora Grandi: University of California Davis
Donald M. Bers: University of California Davis
Sergio Pantano: Group of Biomolecular Simulations, Institute Pasteur de Montevideo
Manuela Zaccolo: Anatomy and Genetics, University of Oxford

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Compartmentalized cAMP/PKA signalling is now recognized as important for physiology and pathophysiology, yet a detailed understanding of the properties, regulation and function of local cAMP/PKA signals is lacking. Here we present a fluorescence resonance energy transfer (FRET)-based sensor, CUTie, which detects compartmentalized cAMP with unprecedented accuracy. CUTie, targeted to specific multiprotein complexes at discrete plasmalemmal, sarcoplasmic reticular and myofilament sites, reveals differential kinetics and amplitudes of localized cAMP signals. This nanoscopic heterogeneity of cAMP signals is necessary to optimize cardiac contractility upon adrenergic activation. At low adrenergic levels, and those mimicking heart failure, differential local cAMP responses are exacerbated, with near abolition of cAMP signalling at certain locations. This work provides tools and fundamental mechanistic insights into subcellular adrenergic signalling in normal and pathological cardiac function.

Date: 2017
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DOI: 10.1038/ncomms15031

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