The G-protein coupled receptor CMKLR1/ChemR23: Studies on gene regulation, receptor ligand activation, and HIV/SIV co-receptor function

Ulrika Mårtensson

Research output: ThesisDoctoral Thesis (compilation)

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Abstract

In all higher organisms, there is a need for intercellular communication. G-protein coupled receptors (GPCRs), located on the cell surface, play an important role in this communication. Cells synthesize and release signalling molecules (ligands), which produce a specific response only in those cells that have a receptor for that ligand. The total number of GPCRs is estimated to be around 800 where approximately 160 still are "orphans", meaning that the endogenous ligands are unknown.

CMKLR1/ChemR23 is a GPCR that was recently "de-orphanized" when the endogenous ligand, TIG2/chemerin, was isolated from inflammatory fluids and hemofiltrate. The receptor displays a high homology to chemoattractant-like receptors involved in inflammation processes. Sequence is implicated in osseous and cartilage development, and the receptor is also suggested to have a pathophysiological role as one of the co-receptors involved in human and simian immunodeficiency virus (HIV-1 and SIV)-infection of CD4+ immune cells. We have described the genomic organization of cmklr1 in mouse and analysed the regulatory mechanism behind the corresponding receptor expression. Two transcripts of mouse cmklr1 have been identified, cmklr1a and b, which utilize alternative promoters for transcription. We show that four Sp1 transcription factors are involved in cmklr1a promoter activation in mouse NB4 1A3 cells, whereas the transcription factor NFY is important for transcription of cmklr1b in mouse BV2 cells. Cmklr1a shows expression in organs such as heart and lung whereas cmklr1b is suggested to be an inducible transcript up-regulated by stimulation with all-trans retinoic acid (ATRA).

The interaction between CMKLR1/ChemR23 and TIG2/chemerin in mouse has been studied. Mouse TIG2/chemerin was found to activate the mouse receptor, although to a lower degree than for the human receptor. Peptides corresponding to the C-terminus of mouse TIG2/chemerin could activate mouse CMKLR1/ChemR23 but to a lower extent than the human receptor. The

results indicate that the peptide domains necessary for receptor activation differ for human and mouse TIG2/chemerin or that the maximal response of the mouse receptor is lower than in human.

The importance of human CMKLR1/ChemR23 as a co-receptor for HIV and SIV has been investigated. We show that CMKLR1/ChemR23 can function as a minor co-receptor for select HIV-1 isolates as well as more generally for HIV-2 and SIV isolates. Among certain better-characterized co-receptors, the HIV-1 co-receptor function of

CMKLR1/ChemR23 resembles that of the chemokine receptor, CCR3. Using a "humanized" hybrid rat CMKLR1/ChemR23 receptor as model, it was shown that the major determinants for HIV-1 and HIV-2 interaction with the receptor reside to a varying degree in the N-terminus and second extracellular loop, whereas the viral interaction in the case of SIV primarily involves the second extracellular loop.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Drug Target Discovery
Supervisors/Advisors
  • Olde, Björn, Supervisor
Award date2005 Apr 2
Publisher
Print ISBNs91-85439-24-x
Publication statusPublished - 2005

Bibliographical note

Defence details

Date: 2005-04-02
Time: 09:15
Place: BioMedical Center (BMC), Segerfalksalen, Sölvegatan 17, Lund

External reviewer(s)

Name: Melhus, Håkan
Title: Professor
Affiliation: Department of Medical Sciences, Uppsala University, Sweden

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<div class="article_info">Ulrika E. A. Mårtensson, Christer Owman and Björn Olde. <span class="article_issue_date">2004</span>. <a href="javascript:downloadFile(544461)" class="article_link">Genomic organization and promoter analysis of the gene encoding the mouse chemoattractant-like receptor, CMKLR1.</a> <span class="journal_series_title">Gene</span>, <span class="journal_volume">vol 328</span> <span class="journal_pages">pp 167-176</span>. <span class="journal_distributor">Elsevier</span></div>
<div class="article_info">Ulrika E. A. Mårtensson, Jesper Bristulf, Christer Owman and Björn Olde. <span class="article_issue_date"></span>. <a href="javascript:downloadFile(544462)" class="article_link">The mouse chemerin receptor gene, mcmklr1, utilizes alternative promoters for transcription and is regulated by all-trans retinoic acid.</a> <span class="journal_series_title">Gene</span>, <span class="journal_distributor">Elsevier</span> (inpress)</div>
<div class="article_info">Ulrika E. A. Mårtensson, Knut Kotarsky, Niclas E. Nilsson, Christer Owman and Björn Olde. <span class="article_issue_date"></span>. <span class="article_title">C-terminal domains of the TIG2/chemerin ligand, required for activation of its receptor CMKLR1/ChemR23, differ in mouse and human.</span> (manuscript)</div>
<div class="article_info">Ulrika E. A. Mårtensson, Eva-Maria Fenyö, Björn Olde and Christer Owman. <span class="article_issue_date"></span>. <span class="article_title">Characterization of the human chemerin receptor ChemR23/CMKLR1 as co-receptor for human and simian immunodeficiency virus infection, and identification of virus-binding receptor domains.</span> (manuscript)</div>

Subject classification (UKÄ)

  • Pharmacology and Toxicology

Keywords

  • Medicin (människa och djur)
  • Medicine (human and vertebrates)
  • HIV/SIV
  • TIG2/chemerin
  • transcriptional regulation
  • ligand activation
  • Co-receptor
  • GPCR
  • ChemR23/CMKLR1

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