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2018 ; 8
(1
): 3023
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Inactivation of TRPM7 kinase in mice results in enlarged spleens, reduced T-cell
proliferation and diminished store-operated calcium entry
#MMPMID29445164
Beesetty P
; Wieczerzak KB
; Gibson JN
; Kaitsuka T
; Luu CT
; Matsushita M
; Kozak JA
Sci Rep
2018[Feb]; 8
(1
): 3023
PMID29445164
show ga
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 Ca(2+) 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 Ca(2+) and Mg(2+) concentrations.
At a fixed [Mg(2+)(o)] of ~0.4?mM, Ca(2+)(o) stimulated proliferation with a
steep concentration dependence and vice versa, at a fixed [Ca(2+)(o)] of ~0.4?mM,
Mg(2+)(o) positively regulated proliferation but with a shallower dependence.
Proliferation was significantly lower in KD mouse than in wildtype at all Ca(2+)
and Mg(2+) concentrations. Ca(2+) 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.