title: Sustained exposure to catecholamines affects cAMP/PKA compartmentalised signalling in adult rat ventricular myocytes.
abstract: 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.
authors.affiliation: Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Fields
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koschinski
authors.affiliation: 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.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zaccolo
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D006332:Cardiomegaly / Q000473:pathology; D002395:Catecholamines / Q000494:pharmacology*; D002451:Cell Compartmentation / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000494:pharmacology; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D002395:Catecholamines; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D009638:Norepinephrine
keywords: CAMP; Cardiac hypertrophy; Phosphodiesterases; Protein kinase a