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Cardiac 5-HT Receptor Signalling

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Cardiac 5-HT Receptor Signalling Cardiac 5-HT4 receptor signalling: Regulation by phosphodiesterases and cross-talk with cGMP signalling pathways. Sabine Weninger Promotor Prof. Dr. R.A. Lefebvre Faculty of Medicine and Health Sciences Heymans Institute of Pharmacology 2014 Thesis submitted as partial fulfilment of the requirements for the degree of Doctor in Medical Sciences Cardiac 5-HT4 receptor signalling: Regulation by phosphodiesterases and cross-talk with cGMP signalling pathways. Sabine Weninger Promotor: Prof. Dr. R.A. Lefebvre Faculty: Faculty of Medicine and Health Sciences Department: Heymans Institute of Pharmacology Year: 2014 Thesis submitted as partial fulfilment of the requirements for the degree of Doctor in Medical Sciences The research of this thesis was financially supported by a doctoral bursary from the Special Investigation Fund of Ghent University and by grant G.0061.08 from the Fund for Scientific Research Flanders (FWO-Vlaanderen). Table of Contents I Literature survey....................................................................................................................... 2 I.1 Excitation-contraction (E-C) coupling in the heart ............................................................ 2 I.2 Regulation of cardiac contractility by sympathetic stimulation ....................................... 4 I.2.1 General....................................................................................................................... 4 I.2.2 Signalling pathway of G protein-coupled receptors (GPCRs) with focus on β- adrenergic receptors .................................................................................................. 5 I.2.3 Regulation of cAMP signalling (focus on β-adrenergic regulation of heart function) ................................................................................................................................... 7 I.3 What is 5-HT? General information and research history .............................................. 14 I.4 Agonists and antagonists ................................................................................................ 18 I.5 5-HT and its receptors in the cardiovascular system ...................................................... 18 I.5.1 5-HT1 receptors ........................................................................................................ 19 I.5.2 5-HT2 receptors ........................................................................................................ 20 I.5.3 The 5-HT3 receptor................................................................................................... 21 I.5.4 The 5-HT4 receptor................................................................................................... 22 I.5.5 5-ht5 receptors ......................................................................................................... 22 I.5.6 The 5-HT6 receptor................................................................................................... 22 I.5.7 The 5-HT7 receptor................................................................................................... 22 I.6 5-HT4 receptors ............................................................................................................... 23 I.6.1 Protein and gene structure ...................................................................................... 23 I.6.2 Coupling to G proteins and desensitization ............................................................. 26 I.6.3 5-HT4 receptor signalling pathway and regulation .................................................. 27 I.7 5-HT4 receptors in the heart ........................................................................................... 29 I.8 References ....................................................................................................................... 31 II Aims ........................................................................................................................................ 48 II.1 References ....................................................................................................................... 50 III Study of the regulation of the inotropic response to 5-HT4 receptor activation via phosphodiesterases and its cross-talk with C-type natriuretic peptide in porcine left atrium . ................................................................................................................................................ 54 III.1 Abstract ........................................................................................................................... 54 III.2 Introduction .................................................................................................................... 56 III.3 Methods .......................................................................................................................... 58 i III.3.1 Tissue preparation ................................................................................................... 58 III.3.2 Experimental protocols ............................................................................................ 58 III.3.3 Data analysis ............................................................................................................ 59 III.3.4 Statistics ................................................................................................................... 60 III.3.5 Drugs ........................................................................................................................ 60 III.4 Results ............................................................................................................................. 61 III.4.1 Effects of the 5-HT4 receptor agonist RS67333 on muscle contractility (unpublished results) ..................................................................................................................... 61 III.4.2 Influence of pre-incubation with selective PDE inhibitors on the responses to 5-HT, prucalopride and RS67333 (unpublished results for RS67333) ............................... 62 III.4.3 Influence of cGMP elevating agents on responses to 5-HT ..................................... 67 III.4.4 Influence of IBMX, when added 60 min after 5-HT or prucalopride ....................... 70 III.4.5 Influence of caveolae and Gi proteins on contractile responses to 5-HT (unpublished results) ............................................................................................... 71 III.5 Discussion ........................................................................................................................ 73 III.5.1 Maintenance of the PDE-mediated control of the inotropic response to 5-HT4 receptor agonists; no evidence for a role of Gi proteins or caveolae ..................... 74 III.5.2 PDE isoforms involved in controlling the inotropic response to 5-HT4 receptor agonists .................................................................................................................... 77 III.5.3 Interaction of cGMP and cAMP pathways ............................................................... 79 III.5.4 Influence of PDE inhibition on the lusitropic responses to 5-HT4 receptor agonists ................................................................................................................................. 81 III.6 Acknowledgements ......................................................................................................... 83 III.7 Conflict of interest ........................................................................................................... 83 III.8 References ....................................................................................................................... 83 IV Influence of phosphodiesterases and cGMP on cAMP generation and on phosphorylation of phospholamban and troponin I by 5-HT4 receptor activation in porcine left atrium ............ 90 IV.1 Abstract ........................................................................................................................... 90 IV.2 Introduction .................................................................................................................... 91 IV.3 Methods .......................................................................................................................... 92 IV.3.1 Tissue preparation ................................................................................................... 92 IV.3.2 Experimental protocols ............................................................................................ 93 IV.3.3 Western Blot Analysis .............................................................................................. 93 IV.3.4 cAMP and cGMP content ......................................................................................... 94 IV.3.5 Data analysis and statistics ...................................................................................... 95 ii IV.3.6 Drugs ........................................................................................................................ 95 IV.4 Results ............................................................................................................................. 96 IV.4.1 Effect of PDE inhibition on cardiac responses, cAMP generation and PLB and TnI phosphorylation by 5-HT ......................................................................................... 96 IV.4.2 Effect of PDE inhibition on cardiac responses, cAMP
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