The G protein-coupled receptor GPR30 signalosome - A novel G protein-independent
mechanism regulating cAMP signaling and receptor trafficking
Broselid, Stefan
2014
Link to publication
Citation for published version (APA):
Broselid, S. (2014). The G protein-coupled receptor GPR30 signalosome - A novel G protein-independent
mechanism regulating cAMP signaling and receptor trafficking. Drug Target Discovery.
Total number of authors:
1
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The G protein-coupled receptor
GPR30 signalosome
A novel G protein-independent mechanism regulating cAMP
signaling and receptor trafficking
by
Stefan Broselid
DOCTORAL DISSERTATION
With the approval from the Faculty of Medicine, Lund University, the public defense of
this thesis will be defended on January 9, 2015, at 13:00 in Segerfalksalen, Biomedicinskt
centrum, Sölvegatan 19, Lund.
Faculty opponent
Professor Graeme Milligan
University of Glasgow
Organization: LUND UNIVERSITY Document name DOCTORAL DISSERTATION Date of issue Author(s): Stefan Broselid Sponsoring organization Title and subtitle
The G protein-coupled receptor GPR30 signalosome
A novel G protein-independent mechanism regulating cAMP signaling and receptor trafficking Abstract
The large protein family called G Protein-coupled receptors (GPCRs) has co-evolved with life throughout evolution; from single cell organisms all the way to complex beings such as us humans. The fact that GPCRs are involved in essentially every physiological event, and that ~50% of drugs on the current market are either directly or indirectly targeted towards the function of GPCRs, we can be certain of their considerable importance.
This thesis is dedicated solely to one particular GPCR, GPR30. This receptor is shrouded in uncertainty with contradictory results and opposing views on effectors and subcellular localization. The aim of this thesis was to elucidate the signaling and membrane trafficking of GPR30 in addition to look for any binding partners.
My primary findings were:
(1) GPR30 constitutively internalizes without any need for ligand binding. (2) GPR30 associates with cytokeratin filaments
(3) GPR30 expression in ER+ breast cancer is a favorable prognostic marker for distant-disease-free survival.
(4) GPR30 confer some constitutive pro-apoptotic signaling but also readily sensitizes the cells to other apoptotic stimuli.
(5) GPR30 directly associates with RAMP3 in-vivo and in-vitro and RAMP3 expression has an impact on GPR30 subcellular localization in the murine heart.
(6) GPR30 constitutively form a signalosome with Membrane associated guanylate kinase proteins (MAGUKs) and A Kinase Anchoring Protein 5 (AKAP5) through its C-terminal PDZ-motif. PKA-RII, which directly binds to AKAP5, is responsible for the attenuation of cAMP in response to cAMP-elevating agents.
Key words
GPER, GPER1, GPR30, estrogen signaling, G1, MAGUK, AKAP5, PDZ, cAMP Classification system and/or index terms (if any)
Supplementary bibliographical information Language ENGLISH
ISSN and key title 1652-8220 ISBN 978-91-7619-082-1
Recipient’s notes Number of pages 100 Price
Security classification
The G protein-coupled receptor
GPR30 signalosome
A novel G protein-independent mechanism regulating cAMP
signaling and receptor trafficking
by
Stefan Broselid
Group of Drug Target Discovery
Department of Experimental Medical Science
Faculty of Medicine
2015
Cover image:
MDCK cells, fixed and stained with anti-GPR30 antibody, followed by alexa488 anti-donkey
antibody for visualization.
Copyright © Stefan Broselid
Lund University, Faculty of Medicine Doctoral Dissertation Series 2015:2
ISBN 978-91-7619-082-1
ISSN 1652-8220
Printed in Sweden by Media-Tryck, Lund University
Lund 2014
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