Cysteinyl leukotriene type I receptor desensitization sustains Ca(2+)-dependent gene expression

A universal mechanism to turn off a biological response is receptor desensitization, where 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/second messenger pathway, followed by receptor internalization(1). G protein-coupled cysteinyl leukotriene type I (CysLT1) receptors regulate immune cell function and the receptor is an established therapeutic target for allergies including asthma(2). Desensitization of these receptors arises predominantly from protein kinase C-dependent phosphorylation of three serine residues in the receptor C-terminus(3). Physiological concentrations of the receptor agonist LTC(4) evoke repetitive cytoplasmic Ca(2+) oscillations, reflecting regenerative Ca(2+) release from stores that is sustained by Ca(2+) entry through store-operated CRAC channels(4). CRAC channels are tightly linked to expression of the transcription factor c-fos(5), a regulator of numerous genes important to cell growth and development(6). Here we show that abolishing leukotriene receptor desensitization suppresses agonist-driven gene expression. 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. 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.