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G protein-coupled receptor regulation: The role of protein interactions and receptor trafficking

Sandén, Caroline LU (2009) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2009:74.
Abstract
The superfamily of G protein-coupled receptors (GPCR) is the largest gene family in the human genome. GPCR-mediated signaling operates in every human cell, and about 50% of existing clinically useful drugs act through GPCR. Kinins are proinflammatory peptides that are rapidly produced extracellularly following pathological insults and tissue damage. These peptides act through two GPCR subtypes, B1 (B1R) and B2 (B2R), to elicit numerous inflammatory responses including vasodilatiation, increased vascular permeability, and pain. GPER1 (G protein-coupled estrogen receptor 1) has recently been suggested as a novel estrogen receptor. Much controversy surrounds this receptor regarding its subcellular localization and activation. The aim of the... (More)
The superfamily of G protein-coupled receptors (GPCR) is the largest gene family in the human genome. GPCR-mediated signaling operates in every human cell, and about 50% of existing clinically useful drugs act through GPCR. Kinins are proinflammatory peptides that are rapidly produced extracellularly following pathological insults and tissue damage. These peptides act through two GPCR subtypes, B1 (B1R) and B2 (B2R), to elicit numerous inflammatory responses including vasodilatiation, increased vascular permeability, and pain. GPER1 (G protein-coupled estrogen receptor 1) has recently been suggested as a novel estrogen receptor. Much controversy surrounds this receptor regarding its subcellular localization and activation. The aim of the present thesis was to explore the role of receptor trafficking and protein-interactions in kinin receptor regulation, as well as studying the receptor trafficking and signaling of GPER1. B1R forms homo-oligomers, which is required for proper B1R maturation and cell-surface expression. Furthermore, the endopeptidase EP24.15 is able to degrade BK intracellularly and attenuate maximal B2R responsiveness without influencing the potency of BK. Finally, GPER1 is localized both intracellularly and on the cell surface, where it is subject to rapid, constitutive endocytosis. Estrogen was found to elevate the level of cAMP in mouse myotube C2C12 cells, in a GPER1-dependent manner, but it is still not clear whether estrogen is the true agonist for GPER1. Taken together, the present thesis demonstrates the importance of protein-protein interactions and trafficking for B1R, B2R, and GPER1 regulation and activity. Understanding these mechanisms will be of great benefit in drug development by presenting novel drug targets. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Docent Schulte, Gunnar, Karolinska Institutet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
receptor trafficking, B1 receptor, receptor oligomerization, estrogen, GPER1, G protein-coupled estrogen receptor 1, EP24.15, BK, bradykinin, B1R, B2R, B2 receptor, GPCR, receptor maturation
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2009:74
pages
155 pages
publisher
Experimentel medicinsk vetenskap, Lunds Universitet
defense location
Segerfalksalen, BMC A10
defense date
2009-09-07 13:00
ISSN
1652-8220
ISBN
978-91-86253-62-2
language
English
LU publication?
yes
id
f90b8a13-e14a-4495-9e41-ed432e7d0ea8 (old id 1463579)
date added to LUP
2009-08-18 09:34:21
date last changed
2016-09-19 08:44:48
@phdthesis{f90b8a13-e14a-4495-9e41-ed432e7d0ea8,
  abstract     = {The superfamily of G protein-coupled receptors (GPCR) is the largest gene family in the human genome. GPCR-mediated signaling operates in every human cell, and about 50% of existing clinically useful drugs act through GPCR. Kinins are proinflammatory peptides that are rapidly produced extracellularly following pathological insults and tissue damage. These peptides act through two GPCR subtypes, B1 (B1R) and B2 (B2R), to elicit numerous inflammatory responses including vasodilatiation, increased vascular permeability, and pain. GPER1 (G protein-coupled estrogen receptor 1) has recently been suggested as a novel estrogen receptor. Much controversy surrounds this receptor regarding its subcellular localization and activation. The aim of the present thesis was to explore the role of receptor trafficking and protein-interactions in kinin receptor regulation, as well as studying the receptor trafficking and signaling of GPER1. B1R forms homo-oligomers, which is required for proper B1R maturation and cell-surface expression. Furthermore, the endopeptidase EP24.15 is able to degrade BK intracellularly and attenuate maximal B2R responsiveness without influencing the potency of BK. Finally, GPER1 is localized both intracellularly and on the cell surface, where it is subject to rapid, constitutive endocytosis. Estrogen was found to elevate the level of cAMP in mouse myotube C2C12 cells, in a GPER1-dependent manner, but it is still not clear whether estrogen is the true agonist for GPER1. Taken together, the present thesis demonstrates the importance of protein-protein interactions and trafficking for B1R, B2R, and GPER1 regulation and activity. Understanding these mechanisms will be of great benefit in drug development by presenting novel drug targets.},
  author       = {Sandén, Caroline},
  isbn         = {978-91-86253-62-2},
  issn         = {1652-8220},
  keyword      = {receptor trafficking,B1 receptor,receptor oligomerization,estrogen,GPER1,G protein-coupled estrogen receptor 1,EP24.15,BK,bradykinin,B1R,B2R,B2 receptor,GPCR,receptor maturation},
  language     = {eng},
  pages        = {155},
  publisher    = {Experimentel medicinsk vetenskap, Lunds Universitet},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {G protein-coupled receptor regulation: The role of protein interactions and receptor trafficking},
  volume       = {2009:74},
  year         = {2009},
}