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Cysteinyl leukotriene type I receptor desensitization sustains Ca2+-dependent gene expression

Nature volume 482, pages 111–115 (2012)Cite this article

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Abstract

Receptor desensitization is a universal mechanism to turn off a biological response; in this process, the ability of a physiological trigger to activate a cell is lost despite the continued presence of the stimulus. Receptor desensitization of G-protein-coupled receptors involves uncoupling of the receptor from its G-protein or second-messenger pathway followed by receptor internalization1. G-protein-coupled cysteinyl leukotriene type I (CysLT1) receptors regulate immune-cell function and CysLT1 receptors are an established therapeutic target for allergies, including asthma2. Desensitization of CysLT1 receptors arises predominantly from protein-kinase-C-dependent phosphorylation of three serine residues in the receptor carboxy terminus3. Physiological concentrations of the receptor agonist leukotriene C4 (LTC4) evoke repetitive cytoplasmic Ca2+ oscillations, reflecting regenerative Ca2+ release from stores, which is sustained by Ca2+ entry through store-operated calcium-release-activated calcium (CRAC) channels4. CRAC channels are tightly linked to expression of the transcription factor c-fos5, a regulator of numerous genes important to cell growth and development6. Here we show that abolishing leukotriene receptor desensitization suppresses agonist-driven gene expression in a rat cell line. Mechanistically, stimulation of non-desensitizing receptors evoked prolonged inositol-trisphosphate-mediated Ca2+ release, which led to accelerated Ca2+-dependent slow inactivation of CRAC channels and a subsequent loss of excitation–transcription coupling. Hence, rather than serving to turn off a biological response, reversible desensitization of a Ca2+ mobilizing receptor acts as an ‘on’ switch, sustaining long-term signalling in the immune system.

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Figure 1: CysLT1-receptor-dependent c-fos expression requires PKC.
Figure 2: Gene expression to non-desensitizing CysLT1 receptors is rescued by preventing a cytoplasmic Ca 2+ rise.
Figure 3: Ca 2+ -dependent slow inactivation underlies suppression of c-Fos expression to non-desensitizing CysLT1 receptors.
Figure 4: PKC-α regulates CysLT1 receptor-driven c-fos transcription.

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Acknowledgements

This work was supported by Medical Research Council grant support to A.B.P. S.-W. N. held a BBSRC-Glaxo-Smith-Kline studentship. We thank G. Miesenboeck and J. Putney for comments on the manuscript.

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Authors and Affiliations

  1. Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK,

    Siaw-Wei Ng, Daniel Bakowski, Charmaine Nelson, Ravi Mehta & Anant B. Parekh

  2. Department of Ear-Nose-Throat Surgery, John Radcliffe Hospital, Oxford OX3 9DH, UK,

    Robert Almeyda & Grant Bates

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  1. Siaw-Wei Ng
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  7. Anant B. Parekh
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Contributions

S.-W.N. performed and analysed Ca2+ measurements, RT–PCR, western blots and siRNA knockdown. D.B. performed and analysed patch-clamp recordings. C.N. carried out immunocytochemistry. R.M. helped with Ca2+ measurements. R.A. and G.B. supplied human nasal polyps. A.B.P. carried out some patch-clamp experiments, discussed the results, supervised the project and wrote the paper.

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Correspondence to Anant B. Parekh.

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The authors declare no competing financial interests.

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Ng, SW., Bakowski, D., Nelson, C. et al. Cysteinyl leukotriene type I receptor desensitization sustains Ca2+-dependent gene expression. Nature 482, 111–115 (2012). https://doi.org/10.1038/nature10731

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