Human lung mast cells (HLMC) express the Ca²⁺‐activated K⁺ channel K_Ca3.1, which plays a crucial role in their migration to a variety of diverse chemotactic stimuli. K_Ca3.1 activation is attenuated by the β₂‐adrenoceptor and the adenosine A_2A receptor through a G_s‐coupled mechanism independent of cyclic AMP. Prostaglandin E₂ promotes degranulation and migration of mouse bone marrow‐derived mast cells through the G_i‐coupled EP₃ prostanoid receptor, and induces LTC₄ and cytokine secretion from human cord blood‐derived mast cells. However, PGE₂ binding to the G_s‐coupled EP₂ receptor on HLMC inhibits their degranulation. We show that EP₂ receptor engagement closes K_Ca3.1 in HLMC. The EP₂ receptor‐specific agonist butaprost was more potent than PGE₂ in this respect, and the effects of both agonists were reversed by the EP₂ receptor antagonist AH6809. Butaprost markedly inhibited HLMC migration induced by chemokine‐rich airway smooth muscle‐conditioned media. Interestingly, PGE₂ alone was chemotactic for HLMC at high concentrations (1 µM), but was a more potent chemoattractant for HLMC following EP₂ receptor blockade. Therefore, the G_s‐coupled EP₂ receptor closes K_Ca3.1 in HLMC and attenuates both chemokine‐ and PGE₂‐dependent HLMC migration. EP₂ receptor agonists with K_Ca3.1 modulating function may be useful for the treatment of mast cell‐mediated disease.

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