Calcium release-activated Calcium (CRAC) Strom: Die Bedeutung für die humane B-Zell Funktion und die physiologische Signifikanz in humanen Mesothelzellen
Zusammenfassung der Projektergebnisse
A unique feature of the Transient receptor potential melastatin 7 (TRPM7) channel is the fusion of an ion channel with an intrinsic kinase domain. TRPM7 is therefore capable to modulate cellular functions either by the conduction of ions through the pore or by phosphorylation. In this study we present a novel target of TRPM7 regulation by phosphorylation: The store operated Calcium entry (SOCE). TRPM7 deficient B lymphocytes exhibit a strongly impaired SOCE compared to wild type cells, while the cell cycle distribution remains unchanged. Accordingly, blocking TRPM7 with NS8593 or Waixenicin A in wild type B lymphocytes resulted also in a significant decrease in SOCE. Hence, we could show that the TRPM7 activity is acutely linked to SOCE, although TRPM7 itself is not a store operated channel. Using kinase-ineffective TRPM7 proteins we could delineate the modulatory effect of TRPM7. Our results indicate that TRPM7 phosphorylates STIM2, thereby facilitating SOCE. In addition, we show that Ca2+ influx through TRPM7 is also essential for maintaining the endoplasmatic reticulum Ca2+ concentration in resting cells and for refilling of the Ca2+ stores after signaling. In conclusion, we show for the very first time the novel cooperativity between TRPM7 and SOCE to maintain the intracellular Ca2+ homeostasis and so, the plethora of biological functions linked to Ca 2+.
