CysLT1 receptor is a target for extracellular nucleotide-induced heterologous desensitization: a possible feedback mechanism in inflammation
| Autor: | Maria Rosa Accomazzo, Saula Ravasi, Valérie Capra, Monica Grimoldi, Simona Citro, Maria P. Abbracchio, G. Enrico Rovati |
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| Rok vydání: | 2005 |
| Předmět: |
Agonist
P2Y receptor Paclitaxel medicine.drug_class medicine.medical_treatment Biology Peptides Cyclic Second Messenger Systems Uridine Diphosphate Leukotriene D4 Adenosine Triphosphate Downregulation and upregulation Homologous desensitization Chlorocebus aethiops medicine Enzyme-linked receptor Extracellular Animals Humans Receptor Desensitization (medicine) Feedback Physiological Inflammation Receptors Leukotriene Dose-Response Relationship Drug Nucleotides Receptors Purinergic P2 Membrane Proteins Extracellular Fluid Cell Biology U937 Cells Immunohistochemistry Cell biology Biochemistry Gene Expression Regulation COS Cells Calcium Protein Kinases |
| Zdroj: | Journal of cell science. 118(Pt 23) |
| ISSN: | 0021-9533 |
| Popis: | Both cysteinyl-leukotrienes and extracellular nucleotides mediate inflammatory responses via specific G-protein-coupled receptors, the CysLT and the P2Y receptors, respectively. Since these mediators accumulate at sites of inflammation, and inflammatory cells express both classes of receptors, their responses are likely to be crossregulated. We investigated the molecular basis of desensitization and trafficking of the CysLT1 receptor constitutively and transiently expressed in the human monocyte/macrophage-like U937 or COS-7 cells in response to LTD4 or nucleotides. Exposure to agonist induced a rapid homologous desensitization of the CysLT1 receptor [as measured by the reduction in the maximal agonist-induced intracellular cytosolic Ca2+ ([Ca2+]i) transient], followed by receptor internalization (as assessed by equilibrium binding and confocal microscopy). Activation of P2Y receptors with ATP or UDP induced heterologous desensitization of the CysLT1 receptor. Conversely, LTD4-induced CysLT1 receptor activation had no effect on P2Y receptor responses, which suggests that the latter have a hierarchy in producing desensitizing signals. Furthermore, ATP/UDP-induced CysLT1 receptor desensitization was unable to cause receptor internalization, induced a faster recovery of CysLT1 functionality and was dependent upon protein kinase C. By contrast, homologous desensitization, which is probably dependent upon G-protein-receptor kinase 2 activation, induced a fast receptor downregulation and, accordingly, a slower recovery of CysLT1 functionality. Hence, CysLT1 receptor desensitization and trafficking are differentially regulated by the CysLT1 cognate ligand or by extracellular nucleotides. This crosstalk may have a profound physiological implication in the regulation of responses at sites of inflammation, and may represent just an example of a feedback mechanism used by cells to fine-tune their responses. |
| Databáze: | OpenAIRE |
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