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

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Abstract
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.

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