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Projekt
The role of TRPC1 C4 C5 C6 and related proteins for Ca2+ signaling in mast cells
Antragsteller
Professor Dr. Marc Freichel
Fachliche Zuordnung
Dermatologie
Förderung
Förderung von 2009 bis 2017
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 124742924
A sustained elevation of intracellular Ca2+ concentration is an obligatory signal for mast cell activation induced by most stimulants. Recently, several membrane proteins were identified in primary mast cell models that regulate Ca2+ entry either as ion conducting constituents (e.g. Orai1), as direct activators of Ca2+ entry channels (e.g. Stim1) or by functional agonism/antagonism (e.g. SK4, TRPM4). However, numerous additional proteins including members of the TRPC family of cation channels, that are able to build or regulate Ca2+ conducting channels, were identified in mast cells. Despite an extensive search for TRP channel modulators, studies to unravel their function and activation mode in primary cells and on organismic level still rely on experiments using transgenic animals in most cases due to the lack of agonists or antagonists with sufficient potency and specificity. We aim to define new and to refine known communication pathways contributing to agonist-induced [Ca2+]i rise in peritoneal mast cells (PMCs) as a model for mature connective tissue mast cells which differ in many aspects including their Ca2+ signals from other mast cell models. We conduct a systematic expression analysis of genes encoding TRP channels and structurally and functionally related membrane proteins in PMCs. We have identified four TRPC proteins as important regulators of Ca2+ signaling induced by FcεRI-stimulation and Endothelin-1 and aim to identify the underlying channel, the mechanisms by which it regulates Ca2+ entry and its relevance for mast cell functions.
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