Abstract
Using a Trpm4 knockout mouse model, we have shown that TRPM4 proteins constitute Ca2+‐activated non‐selective cation channels in mast cells. TRPM4 critically determines the driving force for Ca2+ influx upon FcepsilonRI receptor stimulation, i.e. Trpm4‐/‐ mast cells display a significantly hyperpolarized membrane potential and increased Ca2+ entry after antigen‐mediated activation compared to WT mast cells. Consequently, degranulation and release of histamine from BMMC's is agente and Trpm4‐/‐ mice display a more severe IgE‐mediated acute passive cutaneous anaphylactic (PCA) response. These results established for the first time the physiological role of TRPM4 channels as critical regulators of Ca2+ entry in mast cells and for the development of acute hypersensitivity reactions in mice. Additional experiments have shown that selected insecticides that ameliorate allergic reactions interact with TRPM4. TRPM4 also critically determines migration of mast cells. In TRPM4‐/‐ mast cells, antigen induced migration and SCF induced chemotaxis are defective. Thus, TRPM4 is a critical regulator of Ca2+ dependent mast cell function. We will extend these results to other cell types expressing TRPM4.
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