The emerging role of Mg2+ availability on B cell receptor signaling (109.4)

Abstract

Abstract Hypomagnesemia in patients, as well as in animal models, results in a weaker humoral immune response. The mechanism underlying this Mg2+ dependent modulation of the humoral response remains undefined. The master regulator of Mg2+ homeostasis, TRPM7, is a unique cation channel with a fused serine/threonine kinase domain. Interestingly, TRPM7 interacts with several phospholipase isoforms including PLCγ2, an essential component of B cell receptor (BCR) signaling. Here we address our hypothesis that in response to environmental availability of Mg2+, TRPM7 acts as a homeostatic sensor to adjust BCR signaling strength by serine/threonine phosphorylation of PLCγ2. We show in the DT40 avian B cell line that PLCγ2-dependent BCR-mediated Ca2+-response is reduced under low Mg2+ conditions. Using in vitro phosphorylation assays and a complementation approach in PLCγ2 deficient DT40 cells, we show that TRPM7 kinase is phosphorylating PLCγ2 resulting in the Mg2+ sensitive modulation of BCR-elicited Ca2+ responses. These findings suggest that TRPM7 actively responds to the availability of environmental Mg2+, in turn regulating downstream BCR signaling responses through serine/threonine phosphorylation of PLCγ2. This novel interaction, between an ion channel kinase and a BCR signaling molecule, could be a key piece of the puzzle in explaining why animal models of nutritional hypomagnesemia have weaker humoral immune responses.