Inactivation of TRPM7 Kinase in Mice Results in Enlarged Spleens, Reduced T-Cell Proliferation and Diminished Store-Operated Calcium Entry

Pavani Beesetty, Krystyna B. Wieczerzak, Jennifer N. Gibson, Taku Kaitsuka, Charles Tuan Luu, Masayuki Matsushita, J. Ashot Kozak

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number3023
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Feb 14 2018

ASJC Scopus Subject Areas

  • General

Keywords

  • Research Support, N.I.H., Extramural
  • Animals
  • Calcium / metabolism*
  • Calcium Channels / metabolism
  • Calcium Signaling / physiology
  • Cell Proliferation / physiology
  • Gene Knock-In Techniques / methods
  • Lymphocyte Activation / physiology
  • Magnesium / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Spleen / pathology
  • Splenomegaly / metabolism
  • Stromal Interaction Molecule 1 / metabolism
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / physiology
  • TRPM Cation Channels / gentics
  • TRPM Cation Channels / metabolism*
  • Calcium Channels
  • Stromal Interaction Molecule 1
  • TRPM Cation Channels
  • Trpm7 protein, mouse
  • Magnesium
  • Calcium

Disciplines

  • Medical Cell Biology
  • Medical Neurobiology
  • Medical Physiology
  • Neurosciences
  • Physiological Processes

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