Inactivation of TRPM7 Kinase in Mice Results in Enlarged Spleens, Reduced T-Cell Proliferation and Diminished Store-Operated Calcium Entry
Document Type
Article
Publication Date
2-2018
Abstract
T lymphocytes enlarge (blast) and proliferate in response to antigens in a multistep program that involves obligatory cytosolic calcium elevations. Store-operated calcium entry (SOCE) pathway is the primary source of Ca2+ in these cells. Here, we describe a novel modulator of blastogenesis, proliferation and SOCE: the TRPM7 channel kinase. TRPM7 kinase-dead (KD) K1646R knock-in mice exhibited splenomegaly and impaired blastogenic responses elicited by PMA/ionomycin or anti-CD3/CD28 antibodies. Splenic T-cell proliferation in vitro was weaker in the mutant compared to wildtype littermates. TRPM7 current magnitudes in WT and KD mouse T cells were, however, similar. We tested the dependence of T-cell proliferation on external Ca2+ and Mg2+ concentrations. At a fixed [Mg2+o] of ~0.4 mM, Ca2+o stimulated proliferation with a steep concentration dependence and vice versa, at a fixed [Ca2+o] of ~0.4 mM, Mg2+o positively regulated proliferation but with a shallower dependence. Proliferation was significantly lower in KD mouse than in wildtype at all Ca2+ and Mg2+ concentrations. Ca2+ elevations elicited by anti-CD3 antibody were diminished in KD mutant T cells and SOCE measured in activated KD splenocytes was reduced. These results demonstrate that a functional TRPM7 kinase supports robust SOCE, blastogenesis and proliferation, whereas its inactivation suppresses these cellular events.
Repository Citation
Beesetty, P.,
Wieczerzak, K. B.,
Gibson, J.,
Kaitsuka, T.,
Luu, C. T.,
Matsushita, M.,
& Kozak, J. A.
(2018). Inactivation of TRPM7 Kinase in Mice Results in Enlarged Spleens, Reduced T-Cell Proliferation and Diminished Store-Operated Calcium Entry. Scientific Reports, 8, 3023.
https://corescholar.libraries.wright.edu/ncbp/1145
