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(1). 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(2). Desensitization of CysLT1 receptors arises predominantly from protein-kinase-C-dependent phosphorylation of three serine residues in the receptor carboxy terminus(3). Physiological concentrations of the receptor agonist leukotriene C-4 (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) 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 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.