University of Groningen Understanding compartmentalized cAMP signaling for potential therapeutic approaches in cardiac disease Musheshe, Nshunge

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University of Groningen

Understanding compartmentalized cAMP signaling for potential therapeutic approaches in

cardiac disease

Musheshe, Nshunge

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Publication date: 2018

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Musheshe, N. (2018). Understanding compartmentalized cAMP signaling for potential therapeutic

approaches in cardiac disease: Insights into the molecular mechanisms of the cAMP-mediated regulation of the cardiac phospholemman-Na+/K+ ATPase complex. University of Groningen.

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Understanding compartmentalized cAMP signaling for

potential therapeutic approaches in cardiac disease

Insights into the molecular mechanisms of the cAMP-mediated regulation of the cardiac phospholemman-Na+_/K+_{ATPase complex}

PhD thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. E. Sterken

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Friday 13 July 2018 at 16.15 hours

by

Nshunge Musheshe

born on 7 May 1989

in Mengo, Uganda

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Supervisors

Prof. M. Schmidt Prof. M. Zaccolo

Assessment Committee

Prof. M.C. Harmsen Prof. J. van der Velden Prof. F. Lezoualc’h

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Understanding compartmentalized cAMP signaling for

potential therapeutic approaches in cardiac disease

Insights into the molecular mechanisms of the cAMP-mediated

regulation of the cardiac phospholemman-Na+_/K+_{ATPase complex}

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The research presented in this thesis was carried out at the Department of Physiology, Anatomy and Genetics at the University of Oxford, UK and at the Department of Molecular Pharmacology at the University of Groningen, The Netherlands. This thesis was financially supported by the British Heart Foundation, (PG/10/75/28537 and RG/17/6/32944), the BHF Centre of Research Excellence, Oxford (RE/13/1/30181), the Graduate School of Science and Engineering (GSSE) and Groningen Research Institute of Pharmacy (GRIP), and the Ubbo Emmius fund provided by the University of Groningen.

Printing of the thesis was financially supported by the University library of the University of Groningen, and the Graduate School of Medical Sciences (GSMS, University of Groningen), and the Groningen Research Institute of Pharmacy (GRIP).

Paranymfs: Vicky Matzaraki and Inge Krabbedam

Cover page and design: Augustin Boisleux of Woolf&Woode Design Consultancy

Printing: Ipskamp Printing / https://www.ipskampprinting.nl ISBN: 978-94-028-1102-5

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INDEX

Chapter 1. ... 1

General Introduction... Chapter 2. ... 25

cAMP: From Long Range Second Messenger to Nanodomain Signaling ... Chapter 3. ... 56

Submicroscopic compartmentalization of cAMP/PKA signaling regulates ion flux at the plasmalemma of cardiac myocytes ... Chapter 4. ... 100

Targeting FRET-based reporters for cAMP and PKA activity using AKAP79 .... Chapter 5. ... 120

General Discussion and Future Perspectives ... Extras... 131

Nederlandse sammenfasseng/Dutch summary ... 132

Acknowledgements ... 143

Curriculum vitae ... 151

List of publications ... 152