The G protein-coupled receptor GPR30 signalosome - A novel G protein-independent mechanism regulating cAMP signaling and receptor trafficking

Research output: ThesisDoctoral Thesis (compilation)

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.

Details

Authors
  • Stefan Broselid
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmacology and Toxicology

Keywords

  • AKAP5, AKAP, MAGUK, cAMP signaling, constitutive signaling, signalosome, GPER, GPR30, GPCR, cytokeratin, RAMP3, apoptotic signaling, breast cancer, PDZ, PDZ-ligand
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2015 Jan 9
Publisher
  • Drug Target Discovery
Print ISBNs978-91-7619-082-1
Publication statusPublished - 2014
Publication categoryResearch

Bibliographic note

Defence details Date: 2015-01-09 Time: 13:00 Place: Segerfalksalen, Sölvegatan 17, BMC A12, Lund. External reviewer(s) Name: Milligan, Graeme Title: Professor Affiliation: University of Glasgow ---

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Related research output

P.M. Lenhart, Stefan Broselid, C.J. Barrick, Fredrik Leeb-Lundberg & Murielle Hellsten Caron, 2013, In: Journal of Molecular Endocrinology. 51, 1, p. 191-202

Research output: Contribution to journalArticle

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