Targeting CRAC channels and leukotriene receptors to suppress mast cell activation
Mast cells are tightly linked to the development of allergies and nasal polyposis, the latter affecting up to 2% of the population. In this issue of the Journal, Di Capite et al (p 1014) report the presence of a novel positive feedback cycle in mast cells that might sustain activation in diseased states. This positive feedback cycle involves interplay between Ca²⁺ release–activated Ca²⁺ (CRAC) channels and cysteinyl leukotriene type I receptors. In both rodent and human mast cells, Ca²⁺ entry through open CRAC channels drives the synthesis and secretion of leukotriene C₄, which then acts in a paracrine manner to generate Ca²⁺ signals that drive further cysteinyl leukotriene production. This feed-forward loop results in an intercellular Ca²⁺ wave that spreads through the mast cell population. The authors report how a combination therapy that targets both proteins is effective at suppressing mast cell activation (see Figure). Importantly, the combination of a moderate concentration of a CRAC channel blocker with a modest dose of the cysteinyl leukotriene receptor type I antagonist was as effective at blocking paracrine activation of mast cells as higher concentrations of either drug. This is important clinically because it means that a lower concentration of drugs could be prescribed, reducing the side effects and drug dependence. Read the full article here.

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