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Verfasst von:Arlt, Elisabeth [VerfasserIn]   i
 Tsvilovskyy, Volodymyr [VerfasserIn]   i
 Freichel, Marc [VerfasserIn]   i
Titel:TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity
Verf.angabe:Elisabeth Arlt, Marco Fraticelli, Volodymyr Tsvilovskyy, Wiebke Nadolni, Andreas Breit, Thomas J. O’Neill, Stefanie Resenberger, Gunther Wennemuth, Christian Wahl-Schott, Martin Biel, Christian Grimm, Marc Freichel, Thomas Gudermann, Norbert Klugbauer, Ingrid Boekhoff, and Susanna Zierler
E-Jahr:2020
Jahr:July 28, 2020
Umfang:11 S.
Fussnoten:Published first July 13, 2020 ; Gesehen am 28.09.2020
Titel Quelle:Enthalten in: National Academy of Sciences (Washington, DC)Proceedings of the National Academy of Sciences of the United States of America
Ort Quelle:Washington, DC : National Acad. of Sciences, 1915
Jahr Quelle:2020
Band/Heft Quelle:117(2020), 30, Seite 18068-18078
ISSN Quelle:1091-6490
Abstract:<p>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<sup>2+</sup>) signals. Ca<sup>2+</sup> 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<sup>2+</sup> 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<sup>2+</sup> uptake and filling of endoplasmic reticulum Ca<sup>2+</sup> 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.</p>
DOI:doi:10.1073/pnas.1920122117
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext ; Verlag: https://doi.org/10.1073/pnas.1920122117
 Volltext: https://www.pnas.org/content/117/30/18068
 DOI: https://doi.org/10.1073/pnas.1920122117
Datenträger:Online-Ressource
Sprache:eng
K10plus-PPN:1733881689
Verknüpfungen:→ Zeitschrift

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