The carboxyl terminus of the chemokine receptor CCR3 contains distinct domains which regulate chemotactic signaling and receptor down-regulation in a ligand-dependent manner
✍ Scribed by Ian Sabroe; Annelies Jorritsma; Victoria E. L. Stubbs; Georgina Xanthou; Louise A. Jopling; Paul D. Ponath; Timothy J. Williams; Philip M. Murphy; James E. Pease
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- English
- Weight
- 350 KB
- Volume
- 35
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
Abstract
The chemokine receptor CCR3 regulates the chemotaxis of leukocytes implicated in allergic disease, such as eosinophils. Incubation of eosinophils with CCL11, CCL13 or CCL5 resulted in a rapid decrease of cell‐surface CCR3 which was replicated using CCR3 transfectants. Progressive truncation of the CCR3 C terminus by 15 amino acids produced three constructs, Δ340, Δ325 and Δ310. Δ340 and Δ325 were able to bind CCL11 with affinities similar to wild‐type CCR3. Δ340 transfectants exhibited enhanced migration and reduced receptor down‐regulation in response to CCL11 and CCL13. Δ325 transfectants displayed chemotactic responses to CCL11 and CCL13 similar to wild‐type CCR3, and had impaired down‐regulation when stimulated with CCL13 but not CCL11. In contrast, neither the Δ325 nor Δ340 truncation affected chemotaxis or receptor down‐regulation induced by CCL5. Δ310 transfectants bound CCL11 poorly and were biologically inactive. Inhibitors of p38 mitogen‐activated protein kinase and PI3‐kinase antagonized eosinophil shape change responses and chemotaxis of transfectants to CCL11 and CCL13. In contrast, shape change but not chemotaxis was sensitive to inhibition of the extracellular signal‐regulated kinase kinase pathway suggesting differential regulation of the two responses. Thus, the CCR3 C terminus contains distinct domains responsible for the regulation of receptor desensitization and for coupling to chemotactic responses.