Cysteinyl leukotriene type i receptor desensitization sustains Ca 2+-dependent gene expression
Ng SW., Bakowski D., Nelson C., Mehta R., Almeyda R., Bates G., Parekh AB.
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-fo s, 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. © 2012 Macmillan Publishers Limited. All rights reserved.