Sustained exposure to catecholamines affects cAMP/PKA compartmentalised signalling in adult rat ventricular myocytes.

Autor: Fields LA; Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK., Koschinski A; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK., Zaccolo M; Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. Electronic address: manuela.zaccolo@dpag.ox.ac.uk.
Jazyk: angličtina
Zdroj: Cellular signalling [Cell Signal] 2016 Jul; Vol. 28 (7), pp. 725-32. Date of Electronic Publication: 2015 Oct 22.
DOI: 10.1016/j.cellsig.2015.10.003
Abstrakt: In the heart compartmentalisation of cAMP/protein kinase A (PKA) signalling is necessary to achieve a specific functional outcome in response to different hormonal stimuli. Chronic exposure to catecholamines is known to be detrimental to the heart and disrupted compartmentalisation of cAMP signalling has been associated to heart disease. However, in most cases it remains unclear whether altered local cAMP signalling is an adaptive response, a consequence of the disease or whether it contributes to the pathogenetic process. We have previously demonstrated that isoforms of PKA expressed in cardiac myocytes, PKA-I and PKA-II, localise to different subcellular compartments and are selectively activated by spatially confined pools of cAMP, resulting in phosphorylation of distinct downstream targets. Here we investigate cAMP signalling in an in vitro model of hypertrophy in primary adult rat ventricular myocytes. By using a real time imaging approach and targeted reporters we find that that sustained exposure to catecholamines can directly affect cAMP/PKA compartmentalisation. This appears to involve a complex mechanism including both changes in the subcellular localisation of individual phosphodiesterase (PDE) isoforms as well as the relocalisation of PKA isoforms. As a result, the preferential coupling of PKA subsets with different PDEs is altered resulting in a significant difference in the level of cAMP the kinase is exposed to, with potential impact on phosphorylation of downstream targets.
(Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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