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

Surdo, N. C. et al. (2017) FRET biosensor uncovers cAMP nano-domains at β-adrenergic targets that dictate precise tuning of cardiac contractility. Nature Communications, 8, 15031. (doi: 10.1038/ncomms15031) (PMID:28425435) (PMCID:PMC5411486)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Zaccolo, Professor Manuela and Berrera, Dr Marco
Authors: Surdo, N. C., Berrera, M., Koschinski, A., Brescia, M., Machado, M. R., Carr, C., Wright, P., Gorelik, J., Morotti, S., Grandi, E., Bers, D. M., Pantano, S., and Zaccolo, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Nature Communications 8: 15031
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
540981Quantitative analysis of cAMP dynamics in cardiac myocytes sub-compartments.Manuela ZaccoloBritish Heart Foundation (BHF)PG/10/75/28537RI NEUROSCIENCE & PSYCHOLOGY