title: Engagement of the EP2 prostanoid receptor closes the K+ channel KCa3.1 in human lung mast cells and attenuates their migration.
abstract: 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.
authors.affiliation: The Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, UK.
authors.forename: S Mark
authors.initials: SM
authors.lastname: Duffy
authors.forename: Glenn
authors.initials: G
authors.lastname: Cruse
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Cockerill
authors.forename: Chris E
authors.initials: CE
authors.lastname: Brightling
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
mesh_terms: 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
chemical_list: 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
references.citation: EMBO J. 2004 Jun 2;23(11):2196-205
references.pmid: 15141163
references.citation: Br J Pharmacol. 2006 Apr;147(7):707-13
references.pmid: 16432506
references.citation: J Clin Invest. 1994 Jan;93(1):371-9
references.pmid: 7904270
references.citation: Am Rev Respir Dis. 1982 Dec;126(6):1034-9
references.pmid: 6185023
references.citation: Gen Pharmacol. 1998 Nov;31(5):715-9
references.pmid: 9809467
references.citation: Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):11051-5
references.pmid: 1438313
references.citation: Biochim Biophys Acta. 1999 Aug 20;1420(1-2):231-40
references.pmid: 10446306
references.citation: Pflugers Arch. 1981 Aug;391(2):85-100
references.pmid: 6270629
references.citation: Blood. 2006 Apr 15;107(8):3243-50
references.pmid: 16357326
references.citation: Thorax. 2002 Aug;57(8):677-82
references.pmid: 12149526
references.citation: J Immunol. 2001 Oct 15;167(8):4261-70
references.pmid: 11591748
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11712-7
references.pmid: 17606905
references.citation: J Immunol. 2002 Oct 15;169(8):4586-93
references.pmid: 12370397
references.citation: J Leukoc Biol. 2000 Jul;68(1):38-46
references.pmid: 10914488
references.citation: Am J Respir Crit Care Med. 2005 May 15;171(10):1103-8
references.pmid: 15879427
references.citation: Am Rev Respir Dis. 1993 Jul;148(1):87-90
references.pmid: 8317820
references.citation: J Allergy Clin Immunol. 2003 Nov;112(5):965-72
references.pmid: 14610489
references.citation: J Immunol. 1988 Jan 15;140(2):571-9
references.pmid: 2447182
references.citation: FASEB J. 2005 Jun;19(8):1006-8
references.pmid: 15817638
references.citation: J Biol Chem. 2007 Apr 20;282(16):11613-7
references.pmid: 17329241
references.citation: Am J Respir Cell Mol Biol. 2007 Nov;37(5):525-31
references.pmid: 17585114
references.citation: J Allergy Clin Immunol. 2004 Jul;114(1):66-72
references.pmid: 15241346
references.citation: Am J Respir Cell Mol Biol. 1994 May;10(5):471-80
references.pmid: 8179909
references.citation: Crit Rev Oncol Hematol. 1999 Jul;31(2):119-33
references.pmid: 10451798
references.citation: N Engl J Med. 2002 May 30;346(22):1699-705
references.pmid: 12037149
references.citation: Am J Pathol. 1996 Dec;149(6):2037-54
references.pmid: 8952537
references.citation: Eur J Immunol. 2007 Jun;37(6):1653-62
references.pmid: 17474152
references.citation: Pharmacol Rev. 2006 Dec;58(4):837-62
references.pmid: 17132857
references.citation: Arthritis Rheum. 1997 Mar;40(3):479-89
references.pmid: 9082936
references.citation: Thorax. 2006 Oct;61(10):880-5
references.pmid: 16809411
references.citation: Trends Pharmacol Sci. 2004 May;25(5):280-9
references.pmid: 15120495