Cysteinyl leukotriene type I receptor desensitization sustains Ca2+-dependent gene expression.
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 internalization. G-protein-coupled cysteinyl leukotriene type I (CysLT1) receptors regulate immune-cell function and CysLT1 receptors are an established therapeutic target for allergies, including asthma. Desensitization of CysLT1 receptors arises predominantly from protein-kinase-C-dependent phosphorylation of three serine residues in the receptor carboxy terminus. Physiological concentrations of the receptor agonist leukotriene C(4) (LTC(4)) evoke repetitive cytoplasmic Ca(2+) oscillations, reflecting regenerative Ca(2+) release from stores, which is sustained by Ca(2+) entry through store-operated calcium-release-activated calcium (CRAC) channels. CRAC channels are tightly linked to expression of the transcription factor c-fos, a regulator of numerous genes important to cell growth and development. 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 Ca(2+) release, which led to accelerated Ca(2+)-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 Ca(2+) mobilizing receptor acts as an 'on' switch, sustaining long-term signalling in the immune system.
Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
Siaw-Wei
SW
Ng
Daniel
D
Bakowski
Charmaine
C
Nelson
Ravi
R
Mehta
Robert
R
Almeyda
Grant
G
Bates
Anant B
AB
Parekh
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017997:Leukotriene C4 / Q000494:pharmacology; D008407:Mast Cells; D010768:Phosphoserine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D018077:Receptors, Leukotriene / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology
D016760:Proto-Oncogene Proteins c-fos; D018077:Receptors, Leukotriene; D010768:Phosphoserine; D017997:Leukotriene C4; D019284:Thapsigargin; D011493:Protein Kinase C; C083169:leukotriene D4 receptor; D002118:Calcium