Engagement of the EP₂ prostanoid receptor closes the K⁺ channel KCa3.1 in human lung mast cells and attenuates their migration

Human lung mast cells (HLMC) express the Ca²⁺-activated K⁺ channel KCa3.1, which plays a crucial role in their migration to a variety of diverse chemotactic stimuli. KCa3.1 activation is attenuated by the β₂-adrenoceptor and the adenosine A₂A receptor through a Gs-coupled mechanism independent of cyclic AMP. Prostaglandin E₂ promotes degranulation and migration of mouse bone marrow-derived mast cells through the Gi-coupled EP₃ prostanoid receptor, and induces LTC₄ and cytokine secretion from human cord blood-derived mast cells. However, PGE₂ binding to the Gs-coupled EP₂ receptor on HLMC inhibits their degranulation. We show that EP₂ receptor engagement closes KCa3.1 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 Gs-coupled EP₂ receptor closes KCa3.1 in HLMC and attenuates both chemokine- and PGE₂-dependent HLMC migration. EP₂ receptor agonists with KCa3.1 modulating function may be useful for the treatment of mast cell-mediated disease.