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 Ca(2+)-activated K(+) channel K(Ca)3.1, which plays a crucial role in their migration to a variety of diverse chemotactic stimuli. K(Ca)3.1 activation is attenuated by the beta(2)-adrenoceptor and the adenosine A(2A) receptor through a G(s)-coupled mechanism independent of cyclic AMP. Prostaglandin E(2) promotes degranulation and migration of mouse bone marrow-derived mast cells through the G(i)-coupled EP(3) prostanoid receptor, and induces LTC(4) and cytokine secretion from human cord blood-derived mast cells. However, PGE(2) binding to the G(s)-coupled EP(2) receptor on HLMC inhibits their degranulation. We show that EP(2) receptor engagement closes K(Ca)3.1 in HLMC. The EP(2) receptor-specific agonist butaprost was more potent than PGE(2) in this respect, and the effects of both agonists were reversed by the EP(2) receptor antagonist AH6809. Butaprost markedly inhibited HLMC migration induced by chemokine-rich airway smooth muscle-conditioned media. Interestingly, PGE(2) alone was chemotactic for HLMC at high concentrations (1 microM), but was a more potent chemoattractant for HLMC following EP(2) receptor blockade. Therefore, the G(s)-coupled EP(2) receptor closes K(Ca)3.1 in HLMC and attenuates both chemokine- and PGE(2)-dependent HLMC migration. EP(2) receptor agonists with K(Ca)3.1 modulating function may be useful for the treatment of mast cell-mediated disease.
Duffy
S Mark
SM
The Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, UK.
Cruse
Glenn
G
Cockerill
Sarah L
SL
Brightling
Chris E
CE
Bradding
Peter
P
D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis; D015232:Dinoprostone / Q000378:metabolism; D006636:Histamine Release; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D015221:Potassium Channels / Q000276:immunology* / Q000378:metabolism; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D044004:Xanthones / Q000494:pharmacology
D001562:Benzimidazoles; D002120:Calcium Channel Agonists; C545644:PTGER2 protein, human; D015221:Potassium Channels; D011448:Prostaglandin Antagonists; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone; C102635:1-ethyl-2-benzimidazolinone
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