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The Role of Membrane Trafficking in G Protein-Coupled Receptor Regulation

Enquist, Johan LU (2007)
Abstract
Movements of a receptor in the plasma membrane and within the cell influence receptor function and physiology. I have investigated the role of such movements, generally known as membrane trafficking, in G protein-coupled receptor regulation. My studies show that agonist-promoted internalization and postendocytic sorting determine the degree of resensitization of opioid m (MOR) and d (DOR) receptors, and dopamine D2 (D2R) receptors. Further, postendocytic sorting of DOR and D2R is determined by the non-covalent interaction of the receptors with the protein G protein-coupled associated sorting protein (GASP). Abrogation of the DOR- and D2R-GASP interaction leads to an altered postendocytic fate of the two receptors and results in their... (More)
Movements of a receptor in the plasma membrane and within the cell influence receptor function and physiology. I have investigated the role of such movements, generally known as membrane trafficking, in G protein-coupled receptor regulation. My studies show that agonist-promoted internalization and postendocytic sorting determine the degree of resensitization of opioid m (MOR) and d (DOR) receptors, and dopamine D2 (D2R) receptors. Further, postendocytic sorting of DOR and D2R is determined by the non-covalent interaction of the receptors with the protein G protein-coupled associated sorting protein (GASP). Abrogation of the DOR- and D2R-GASP interaction leads to an altered postendocytic fate of the two receptors and results in their recycling and resensitization. I have also shown that the cognate agonist des-Arg10-kallidin for the G protein-coupled bradykinin B1 receptor (B1R) acts as an inverse agonist on receptor endocytosis and does not cause receptor desensitization. Further, I have mapped the internalization routes utilized by the B1R and bradykinin B2 receptors and isolated the domains necessary for their internalization and postendocytic sorting. In summary, my studies highlight and detail a novel regulatory mode of activity in three receptor groups of great physiological and pharmacological significance in areas such as pain transmission. Further, I show that receptor membrane trafficking can be artificially modulated to impact in vivo receptor function. Thus, my result may be directly utilized for future therapeutic purposes. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Cotecchia, Susanna, Université de Lausanne, Schweiz
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Medicin (människa och djur), Medicine (human and vertebrates), downregulation, recycling, resensitization, desensitization, GPCR, membrane trafficking
pages
87 pages
publisher
Institutionen för Experimentell Medicinsk Vetenskap, Lunds Universitet
defense location
Biomedicinskt Centrum D15 039 Sölvegatan 19 Lund
defense date
2007-01-20 09:00:00
ISBN
91-85559-84-9
language
English
LU publication?
yes
additional info
J Enquist, C Skroder, JL Whistler and LM Leeb-Lundberg. 2007. Kinins promote B2 receptor endocytosis and delay constitutive B1 receptor endocytosis. Mol Pharmacol, vol 71 pp 494-507.
SE Bartlett, J Enquist, FW Hopf, JH Lee, F Gladher, V Kharazia, M Waldhoer, WS Mailliard, R Armstrong, A Bonci and JL Whistler. 2005. Dopamine responsiveness is regulated by targeted sorting of D2 receptors. Proc Natl Acad Sci USA, vol 9;102 pp 11521-6.
JL Whistler, J Enquist, A Marley, J Fong, F Gladher and P Tsuruda. 2002. Modulation of postendocytic sorting of G protein-coupled receptors. Science, vol 26;297 pp 615-20.
id
2462b1fb-abc3-466a-b40d-16e98e88b8fd (old id 547837)
date added to LUP
2016-04-01 17:14:23
date last changed
2018-11-21 20:47:44
@phdthesis{2462b1fb-abc3-466a-b40d-16e98e88b8fd,
  abstract     = {{Movements of a receptor in the plasma membrane and within the cell influence receptor function and physiology. I have investigated the role of such movements, generally known as membrane trafficking, in G protein-coupled receptor regulation. My studies show that agonist-promoted internalization and postendocytic sorting determine the degree of resensitization of opioid m (MOR) and d (DOR) receptors, and dopamine D2 (D2R) receptors. Further, postendocytic sorting of DOR and D2R is determined by the non-covalent interaction of the receptors with the protein G protein-coupled associated sorting protein (GASP). Abrogation of the DOR- and D2R-GASP interaction leads to an altered postendocytic fate of the two receptors and results in their recycling and resensitization. I have also shown that the cognate agonist des-Arg10-kallidin for the G protein-coupled bradykinin B1 receptor (B1R) acts as an inverse agonist on receptor endocytosis and does not cause receptor desensitization. Further, I have mapped the internalization routes utilized by the B1R and bradykinin B2 receptors and isolated the domains necessary for their internalization and postendocytic sorting. In summary, my studies highlight and detail a novel regulatory mode of activity in three receptor groups of great physiological and pharmacological significance in areas such as pain transmission. Further, I show that receptor membrane trafficking can be artificially modulated to impact in vivo receptor function. Thus, my result may be directly utilized for future therapeutic purposes.}},
  author       = {{Enquist, Johan}},
  isbn         = {{91-85559-84-9}},
  keywords     = {{Medicin (människa och djur); Medicine (human and vertebrates); downregulation; recycling; resensitization; desensitization; GPCR; membrane trafficking}},
  language     = {{eng}},
  publisher    = {{Institutionen för Experimentell Medicinsk Vetenskap, Lunds Universitet}},
  school       = {{Lund University}},
  title        = {{The Role of Membrane Trafficking in G Protein-Coupled Receptor Regulation}},
  url          = {{https://lup.lub.lu.se/search/files/4917040/547839.pdf}},
  year         = {{2007}},
}