The ion channel TRPM7 is required for B cell lymphopoiesis

Abstract

The transient receptor potential (TRP) family is a large family of widely expressed ion channels that regulate the intracellular concentration of ions and metals and respond to various chemical and physical stimuli. TRP subfamily M member 7 (TRPM7) is unusual in that it contains both an ion channel and a kinase domain. TRPM7 is a divalent cation channel with preference for Ca and Mg It is required for the survival of DT40 cells, a B cell line; however, deletion of TRPM7 in T cells does not impair their development. We found that expression of TRPM7 was required for B cell development in mice. Mice that lacked TRPM7 in B cells failed to generate peripheral B cells because of a developmental block at the pro-B cell stage. The loss of TRPM7 kinase activity alone did not affect the proportion of peripheral mature B cells or the development of B cells in the bone marrow. However, supplementation with a high concentration of extracellular Mg partially rescued the development of TRPM7-deficient B cells in vitro. Thus, our findings identify a critical role for TRPM7 ion channel activity in B cell development.

Beyond the CRAC: Diversification of ion signaling in B cells

“…This is consistent with the observation that supplementation with high concentrations of extracellular Mg 2+ is able to rescue the growth arrest seen in chicken DT40 B cells deficient in TRPM7 . The discrepancy in the ability of supplementary Mg 2+ to fully support primary murine B‐cell development compared to chicken DT40 B cells may be due to differential expression of other Mg 2+ channels in DT40 vs primary HSCs; indeed, TRPM7‐deficient DT40 cells upregulate the Mg 2+ transporter MagT1 . Our findings also highlight, once again, distinct requirements for ion channels in different hematopoietic lineages.…”

“…To examine a role for TRPM7 in B cells, we generated mice that lacked TRPM7 in the B‐cell lineage using TRPM7‐flox mice expressing Cre recombinase under the pan B cell CD79a (Mb1) gene promoter . We found a complete loss of B220 + CD19 + mature B cells in the spleen, lymph nodes, and peripheral blood, as well as nearly complete loss of B1 B cells in the peritoneum in TRPM7‐deficient mice.…”

“…This superfamily of ion channels is classified into six subfamilies in vertebrates: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polysystin), TRPA (ankyrin), and TRPML (mucolipin), with different modes of activation and selectivity both within subfamilies and across the superfamily. Although many TRP channels are expressed in B cells, to date, only TRPM7 has been demonstrated as critical for B‐cell development …”

“…Our findings also highlight, once again, distinct requirements for ion channels in different hematopoietic lineages. The requirement for TRPM7 may be more pronounced in B cells compared to T cells because T cells, but not B cells, express other Mg 2+ permeable channels such as TRPM6 . It may also be that the Mg 2+ permeable channel, MagT1, has a more important role in T‐cell development …”

“…Magnesium homeostasis is essential for B‐cell development, maintenance, and activation. Conditional knockout of TRPM7 in B cells results in a developmental block at the pro‐B‐cell stage, which has made it difficult to study the importance of magnesium in humoral immune responses. It has been shown, however, that MAGT1‐KO mice have impaired plasma cell numbers preimmunization .…”