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First published online November 23, 2005
doi: 10.1242/10.1242/jcs.02668

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CysLT₁ receptor is a target for extracellular nucleotide-induced heterologous desensitization: a possible feedback mechanism in inflammation

¹ Laboratory of Molecular Pharmacology, Section of Eicosanoid Pharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy
² Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy

^* Author for correspondence (e-mail: genrico.rovati{at}unimi.it)

Accepted 31 August 2005

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.

Key words: CysLT₁ Receptor, Heterologous desensitization, Extracellular nucleotides, Inflammation, U937 cells

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