Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4.
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.
Vennekens
Rudi
R
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
Olausson
Jenny
J
Meissner
Marcel
M
Bloch
Wilhelm
W
Mathar
Ilka
I
Philipp
Stephan E
SE
Schmitz
Frank
F
Weissgerber
Petra
P
Nilius
Bernd
B
Flockerzi
Veit
V
Freichel
Marc
M
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*
D017455:Receptors, IgE; D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse; D007073:Immunoglobulin E; D002118:Calcium