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The TRPM7 channel kinase regulates store‐operated calcium entry
Author(s) -
Faouzi Malika,
Kilch Tatiana,
Horgen F. David,
Fleig Andrea,
Penner Reinhold
Publication year - 2017
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp274006
Subject(s) - trpm7 , microbiology and biotechnology , transient receptor potential channel , chemistry , kinase , endoplasmic reticulum , protein kinase domain , voltage dependent calcium channel , stim1 , trpc1 , calcium channel , calcium , biology , receptor , biochemistry , mutant , organic chemistry , gene
Key points Pharmacological and molecular inhibition of transient receptor potential melastatin 7 (TRPM7) reduces store‐operated calcium entry (SOCE). Overexpression of TRPM7 in TRPM7 −/− cells restores SOCE. TRPM7 is not a store‐operated calcium channel. TRPM7 kinase rather than channel modulates SOCE. TRPM7 channel activity contributes to the maintenance of store Ca 2+ levels at rest.Abstract The transient receptor potential melastatin 7 (TRPM7) is a protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain. In the present study, we report store‐operated calcium entry (SOCE) as a novel target of TRPM7 kinase activity. TRPM7‐deficient chicken DT40 B lymphocytes exhibit a strongly impaired SOCE compared to wild‐type cells as a result of reduced calcium release activated calcium currents, and independently of potassium channel regulation, membrane potential changes or changes in cell‐cycle distribution. Pharmacological blockade of TRPM7 with NS8593 or waixenicin A in wild‐type B lymphocytes results in a significant decrease in SOCE, confirming that TRPM7 activity is acutely linked to SOCE, without TRPM7 representing a store‐operated channel itself. Using kinase‐deficient mutants, we find that TRPM7 regulates SOCE through its kinase domain. Furthermore, Ca 2+ influx through TRPM7 is essential for the maintenance of endoplasmic reticulum Ca 2+ concentration in resting cells, and for the refilling of Ca 2+ stores after a Ca 2+ signalling event. We conclude that the channel kinase TRPM7 and SOCE are synergistic mechanisms regulating intracellular Ca 2+ homeostasis.