TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity.

Autor:	Arlt E; Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 München, Germany., Fraticelli M; Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 München, Germany., Tsvilovskyy V; Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany., Nadolni W; Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 München, Germany., Breit A; Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 München, Germany., O'Neill TJ; Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 München, Germany., Resenberger S; Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 München, Germany., Wennemuth G; Institute for Anatomy, University of Duisburg-Essen, 45147 Duisburg, Germany., Wahl-Schott C; Institute for Neurophysiology, Hannover Medical School, 30625 Hannover, Germany., Biel M; Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 München, Germany., Grimm C; Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 München, Germany., Freichel M; Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany., Gudermann T; Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 München, Germany., Klugbauer N; Institute for Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, Albert-Ludwigs-Universität, 79104 Freiburg, Germany., Boekhoff I; Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 München, Germany; ingrid.boekhoff@lrz.uni-muenchen.de susanna.zierler@lrz.uni-muenchen.de., Zierler S; Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, 80336 München, Germany; ingrid.boekhoff@lrz.uni-muenchen.de susanna.zierler@lrz.uni-muenchen.de.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jul 28; Vol. 117 (30), pp. 18068-18078. Date of Electronic Publication: 2020 Jul 13.
DOI:	10.1073/pnas.1920122117
Abstrakt:	Mast cells and basophils are main drivers of allergic reactions and anaphylaxis, for which prevalence is rapidly increasing. Activation of these cells leads to a tightly controlled release of inflammatory mediators stored in secretory granules. The release of these granules is dependent on intracellular calcium (Ca 2+ ) signals. Ca 2+ release from endolysosomal compartments is mediated via intracellular cation channels, such as two-pore channel (TPC) proteins. Here, we uncover a mechanism for how TPC1 regulates Ca 2+ homeostasis and exocytosis in mast cells in vivo and ex vivo. Notably, in vivo TPC1 deficiency in mice leads to enhanced passive systemic anaphylaxis, reflected by increased drop in body temperature, most likely due to accelerated histamine-induced vasodilation. Ex vivo, mast cell-mediated histamine release and degranulation was augmented upon TPC1 inhibition, although mast cell numbers and size were diminished. Our results indicate an essential role of TPC1 in endolysosomal Ca 2+ uptake and filling of endoplasmic reticulum Ca 2+ stores, thereby regulating exocytosis in mast cells. Thus, pharmacological modulation of TPC1 might blaze a trail to develop new drugs against mast cell-related diseases, including allergic hypersensitivity. Competing Interests: The authors declare no competing interest. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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