title: Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4.
abstract: Mast cells are key effector cells in allergic reactions. Aggregation of the receptor FcepsilonRI in mast cells triggers the influx of calcium (Ca(2+)) and the release of inflammatory mediators. Here we show that transient receptor potential TRPM4 proteins acted as calcium-activated nonselective cation channels and critically determined the driving force for Ca(2+) influx in mast cells. Trpm4(-/-) bone marrow-derived mast cells had more Ca(2+) entry than did TRPM4(+/+) cells after FcepsilonRI stimulation. Consequently, Trpm4(-/-) bone marrow-derived mast cells had augmented degranulation and released more histamine, leukotrienes and tumor necrosis factor. Trpm4(-/-) mice had a more severe IgE-mediated acute passive cutaneous anaphylactic response, whereas late-phase passive cutaneous anaphylaxis was not affected. Our results establish the physiological function of TRPM4 channels as critical regulators of Ca(2+) entry in mast cells.
authors.affiliation: Laboratory of Ion Channel Research, Division of Physiology, Department of Molecular Cell Biology, Campus Gasthuisberg, O&N1, KU Leuven, Herestraat 49 bus 802, B-3000 Leuven, Belgium. rudi.vennekens@med.kuleuven.be
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.forename: Jenny
authors.initials: J
authors.lastname: Olausson
authors.forename: Marcel
authors.initials: M
authors.lastname: Meissner
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.forename: Ilka
authors.initials: I
authors.lastname: Mathar
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Philipp
authors.forename: Frank
authors.initials: F
authors.lastname: Schmitz
authors.forename: Petra
authors.initials: P
authors.lastname: Weissgerber
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
mesh_terms: D000707:Anaphylaxis / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology*; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D018408:Patch-Clamp Techniques; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: D017455:Receptors, IgE; D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse; D007073:Immunoglobulin E; D002118:Calcium