Document Detail


A single nucleotide polymorphism in the CCR3 gene ablates receptor export to the plasma membrane.
MedLine Citation:
PMID:  20541248     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: The chemokine receptor CCR3 orchestrates the migration of eosinophils, basophils, T(H)2 lymphocytes, and mast cells during the allergic response, with CCR3 blockade a potential means of therapeutic intervention. Non-synonymous single nucleotide polymorphisms (SNPs) within the ccr3 gene have previously been described, with little information regarding their effects on CCR3 function. OBJECTIVE: To characterize the effects of nonsynonymous SNPs within the ccr3 gene. METHODS: Site-directed mutagenesis was used to generate N-terminally tagged mutant CCR3 constructs corresponding to reported SNPs. Cell transfectants expressing either wild-type or mutant CCR3 were studied by flow cytometry, Western blotting, and confocal microscopy and examined for their ability to migrate to the CC chemokine ligand CCL11/eotaxin. RESULTS: An L324P mutant CCR3 protein corresponding to the previously identified T971C SNP was not expressed at the cell surface, and cells remained unresponsive to CCL11 in chemotaxis assays. Confocal microscopy confirmed that L324P-CCR3 had a predominantly intracellular distribution compared with wild-type CCR3. A L324A variant of CCR3 had an identical phenotype to the L324P mutant, suggesting that L324 per se is critical for successful trafficking of nascent CCR3 to the cell membrane. The processes involved appear to be specific for CCR3, because an identical mutation in the homologous receptor CCR1 had minor effects. CONCLUSION: Trafficking to the cell surface of nascent CCR3 is critically dependent on a C-terminal leucine residue, suggestive of specific mechanisms for CCR3 export. Manipulation of these mechanisms may suggest novel means of antagonizing CCR3 function in the treatment of allergy.
Authors:
Emma L Wise; Kandace T Bonner; Timothy J Williams; James E Pease
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-11
Journal Detail:
Title:  The Journal of allergy and clinical immunology     Volume:  126     ISSN:  1097-6825     ISO Abbreviation:  J. Allergy Clin. Immunol.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-12     Completed Date:  2010-07-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1275002     Medline TA:  J Allergy Clin Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  150-7.e2     Citation Subset:  AIM; IM    
Copyright Information:
Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
Affiliation:
Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line, Tumor
Cell Membrane / metabolism*
Endoplasmic Reticulum / metabolism
Golgi Apparatus / metabolism
Lysosomes / metabolism
Mice
Mutagenesis, Site-Directed
Polymorphism, Single Nucleotide*
Protein Transport
Receptors, CCR3 / chemistry,  genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
076036/Z/04/Z//Wellcome Trust
Chemical
Reg. No./Substance:
0/Ccr3 protein, mouse; 0/Receptors, CCR3
Comments/Corrections
Comment In:
J Allergy Clin Immunol. 2010 Jul;126(1):158-9   [PMID:  20542325 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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