TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity, 2020, Arlt et al

[Andy]

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 (Ca2+) signals. Ca2+ 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 Ca2+ 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 Ca2+ uptake and filling of endoplasmic reticulum Ca2+ 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.

Open access, https://www.pnas.org/content/early/2020/07/10/1920122117

Press release, https://www.en.uni-muenchen.de/news/newsarchiv/2020/zierler_ionenkanal.html

 

[wigglethemouse]

I've come to realise that all these papers that look at one protein and it's effect on one particular cell are interesting, but cells have a large number of receptors and many things can affect them. TPC1 will only be one of many. In addition TPC1 has other effects that may have major consequences on health not related to mast cells. This is from Gene Cards for the gene TPCN1 that encodes protein TPC1.

GeneCards Summary for TPCN1 Gene
TPCN1 (Two Pore Segment Channel 1) is a Protein Coding gene. Diseases associated with TPCN1 include Thyroid Gland Follicular Carcinoma and Thyroid Gland Cancer. Among its related pathways are Calcium signaling pathway and Transport of glucose and other sugars, bile salts and organic acids, metal ions and amine compounds. Gene Ontology (GO) annotations related to this gene include identical protein binding and voltage-gated calcium channel activity. An important paralog of this gene is CACNA1B.

Source : https://www.genecards.org/cgi-bin/carddisp.pl?gene=TPCN1

In addition there are many other calcium channels that could also play an effect.........

Here is just the first hit on a search of "mast cells calcium". There are many many things that affect calcium signalling in mast cells.
REGULATORS OF CA2+ SIGNALING IN MAST CELLS Potential Targets for Treatment of Mast-Cell Related Diseases?
https://www.ncbi.nlm.nih.gov/books/NBK45036/

A calcium signal is essential for degranulation, generation of eicosanoids and optimal production of cytokines in mast cells in response to antigen and other stimulants.

The signal is initiated by phospholipase C-mediated production of inositol 1,4,5-trisphosphate resulting in release of stored Ca2+ from the endoplasmic reticulum (ER) and Golgi.

Depletion of these stores activates influx of extracellular Ca2+, usually referred to as store-operated calcium entry (SOCE), through the interaction of the Ca2+-sensor, stromal interacting molecule-1 (STIM1), in ER with Orai1(CRACM1) and transient receptor potential canonical (TRPC) channel proteins in the plasma membrane (PM). This interaction is enabled by microtubular-directed reorganization of ER to form ER/PM contact points or "punctae" in which STIM1 and channel proteins colocalize.

The ensuing influx of Ca2+ replenishes Ca2+ stores and sustains elevated levels of cytosolic Ca2+ ions-the obligatory signal for mast-cell activation. In addition, the signal can acquire spatial and dynamic characteristics (e.g., calcium puffs, waves, oscillations) that encode signals for specific functional outputs. This is achieved by coordinated regulation of Ca2+ fluxes through ATP-dependent Ca2+-pumps and ion exchangers in mitochondria, ER and PM.

As discussed in this review, studies in mast cells revealed much about the mechanisms described above but little about allergic and autoimmune diseases although studies in other types of cells have exposed genetic defects that lead to aberrant calcium signaling in immune diseases. Pharmacologic agents that inhibit or activate the regulatory components of calcium signaling in mast cells are also discussed along with the prospects for development of novel SOCE inhibitors that may prove beneficial in the treatment inflammatory mast-cell related diseases.