Regulation of TRPM7 channel kinase under hypo and hypermagnesemic conditions

The National Institute of Allergy and Infectious Diseases awarded Wright State University $540,878 on September 2, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the regulation of the TRPM7 ion channel and kinase under conditions of magnesium deficiency and excess.

The research examines how TRPM7, a dual-function protein expressed at high levels in immune cells, regulates T-cell activation and macrophage function when intracellular magnesium levels vary. The project uses a novel heterozygous mouse model in which a single amino acid substitution renders TRPM7 channels constitutively active by reducing magnesium sensitivity, allowing researchers to isolate and study ion channel activity separately from the protein's kinase function. Prior global knockout studies have proven lethal in embryos, making this targeted approach necessary to understand whether observed immune and cellular phenotypes result from ion flux or phosphotransferase activity. Given that approximately 25 percent of the U.S. population is magnesium deficient, and hypermagnesemia frequently accompanies kidney disease, understanding these calcium and magnesium signaling pathways in immune function addresses a significant gap in knowledge.

Work is performed in Dayton, Ohio. The period of performance runs from September 2, 2026, through August 31, 2029. The assistance type is a Project Grant.

Abstract

T lymphocyte activation and proliferation is essential for the human adaptive immune response. Calcium and magnesium signaling pathways play a crucial role in this process, and their defects result in various forms of immunodeficiency and muscle disorders. ~25% of the U.S. Population is magnesium deficient, which compromises immune response among other pathways. Thus, IT is urgent to fully understand these understudied pathways and their impact on immune function. Hypermagnesemia, often accompanies kidney injury and disease. Several players involved in calcium and magnesium transport have been identified at the molecular level. One of them, TRPM7, a protein with dual ION channel and serine/threonine kinase function, is permeable to both calcium and magnesium. IT is regulated by intracellular ionized magnesium. TRPM7 is highly expressed in immune cells and is required for t-cell development and activation of macrophages. Because of the channel- enzyme duality of TRPM7, overexpression or knockdown of the full gene do not address whether ION flux or phosphotransferase activity underlies observed phenotypes. Global knockout of TRPM7 gene in mice results in embryonic lethality. In order to examine TRPM7 ION transport and kinase functions separately, we have generated a novel heterozygous mouse model, stemming from our recent biophysical studies of magnesium and PH sensitivity. Under normal or hypermagnesemic conditions, the majority of TRPM7 channels are inhibited by cytoplasmic magnesium, whereas the kinase is constitutively active. In the new mutant mouse, a single amino acid substitution in TRPM7 reduced the channel's magnesium sensitivity, making the channels constitutively active. In this proposal, we aim to investigate the contribution of TRPM7 channel activity to t-cell and macrophage function under normal, hypo and hypermagnesemic conditions. As extracellular magnesium levels strongly influence immune cells, we will determine whether TRPM7 channel serves as the main magnesium entry pathway, or the kinase is responsible for the cellular phenotype. We propose these specific aims: aim 1: generate and characterize a TRPM7 channel mutant mouse model to elucidate TRPM7 channel/kinase signaling in macrophages and lymphocytes, which are critical immune responders. Aim 2: investigate TRPM7 channel and kinase properties in conditions of MG2+ deficiency and excess. Aim 3: define MG2+ and cytotoxic divalent metal cation entry, which can impact the immune response. Completion of these aims are expected to characterize the import of magnesium balance/sufficiency in several pathways vital to human health, including immune function.