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

Johan Enquist

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

139 Nedladdningar (Pure)

Sammanfattning

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.
Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
  • Institutionen för experimentell medicinsk vetenskap
Handledare
  • Leeb-Lundberg, Fredrik, handledare
Tilldelningsdatum2007 jan. 20
Förlag
ISBN (tryckt)91-85559-84-9
StatusPublished - 2007

Bibliografisk information

Defence details

Date: 2007-01-20
Time: 09:00
Place: Biomedicinskt Centrum D15 039 Sölvegatan 19 Lund

External reviewer(s)

Name: Cotecchia, Susanna
Title: Professor
Affiliation: Université de Lausanne, Schweiz

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<div class="article_info">J Enquist, C Skroder, JL Whistler and LM Leeb-Lundberg. <span class="article_issue_date">2007</span>. <span class="article_title">Kinins promote B2 receptor endocytosis and delay constitutive B1 receptor endocytosis.</span> <span class="journal_series_title">Mol Pharmacol</span>, <span class="journal_volume">vol 71</span> <span class="journal_pages">pp 494-507</span>.</div>
<div class="article_info">SE Bartlett, J Enquist, FW Hopf, JH Lee, F Gladher, V Kharazia, M Waldhoer, WS Mailliard, R Armstrong, A Bonci and JL Whistler. <span class="article_issue_date">2005</span>. <span class="article_title">Dopamine responsiveness is regulated by targeted sorting of D2 receptors.</span> <span class="journal_series_title">Proc Natl Acad Sci USA</span>, <span class="journal_volume">vol 9;102</span> <span class="journal_pages">pp 11521-6</span>.</div>
<div class="article_info">JL Whistler, J Enquist, A Marley, J Fong, F Gladher and P Tsuruda. <span class="article_issue_date">2002</span>. <span class="article_title">Modulation of postendocytic sorting of G protein-coupled receptors.</span> <span class="journal_series_title">Science</span>, <span class="journal_volume">vol 26;297</span> <span class="journal_pages">pp 615-20</span>.</div>

Ämnesklassifikation (UKÄ)

  • Medicinska grundvetenskaper

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