Digital Public Defence: Marie-Victoire Louise Augusta Cosson

MSc Marie-Victoire Louise Augusta Cosson at Institute of Clinical Medicine will be defending the thesis “Role of adenylyl cyclase subtypes, inhibitory G protein and phosphodiesterases to regulate the β1-AR-mediated inotropic response” for the degree of PhD (Philosophiae Doctor).

The public defence will be held as a video conference over Zoom.

The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.

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Digital Trial Lecture – time and place

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Adjudication committee

  • First opponent: Professor Roland Seifert, Institute of Pharmacology, Hannover Medical School, Germany
  • Second opponent: Professor Julia Gorelik, Faculty of Medicine, National Heart & Lung Institute, Imperial College London, UK
  • Third member and chair of the evaluation committee: Professor Håvard Attramadal, Faculty of Medicine, University of Oslo

Chair of the Defence

Professor II William E. Louch, Faculty of Medicine, University of Oslo

Principal Supervisor

Researcher Kurt Allen Krobert, Faculty of Medicine, University of Oslo

Summary

In the heart, activation of the sympathetic nervous system increases the force of contraction, heart rate and relaxation primarily through activation of β-adrenergic G-protein-coupled receptors (βAR). The β1AR is the dominant subtype in the heart and most of the functional responses to βAR-agonists are attributed to β1AR and β2ARs. Although both β1AR and β2ARs respond to noradrenaline and adrenaline, subcellular compartmentation of the downstream signaling proteins allows for distinct functional properties which mediate a variety of biological roles. Compartmentation is achieved by various proteins that regulate the signaling pathway spatially and temporally. β1AR signaling and its ability to increase contractile force is regulated by at least inhibitory G protein (Gi), phosphodiesterases (PDEs) and adenylyl cyclase (AC), of which isoforms 5 and 6 are most prevalent in the heart. The first aim of this study was to determine if the β1AR-mediated inotropic response was dependent upon a particular AC subtype.  Second, determine if a tonic inhibitory effect of Gi that we previously discovered was specific to either AC5 or AC6. Lastly, elucidate the role of PDE3 and PDE4 to regulate β1AR-mediated increases in cAMP levels and to correlate them with the β1AR-mediated inotropic response. To this end, we utilized AC5 and AC6 knockout mice. Our data indicate that the β1AR-mediated inotropic response can be mediated through either AC5 or AC6 isoforms, implying functional redundancy.  Furthermore, the β1AR-mediated functional response through both AC isoforms is regulated by receptor independent constitutively active Gi, and lastly we demonstrate that PDE4 is the primary regulator of β1AR signaling through AC6. Taken together, these data suggest that subcellular compartmentation of the upstream cAMP signaling pathway leads to different downstream physiological responses.

Additional information

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Published Sep. 4, 2020 11:26 AM - Last modified Sep. 21, 2020 1:28 PM