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Role of enzyme-coupled TRP channels in immune cell function

Final Report Summary - RETIF (Role of enzyme-coupled TRP channels in immune cell function)

Among the mammalian transient-receptor-potential (TRP) cation channel superfamily, the TRPM subfamily, named after its founding member melastatin, comprises the dual-function protein TRPM7. TRPM7 is a divalent-selective cation channel, conducting Mg2+, Ca2+ and Zn2+, fused to a C-terminal alpha-kinase domain. TRPM7 has been implicated in cell survival, proliferation, apoptosis as well as migration and immune cell function. However, the physiologic role of the protein’s channel or enzymatic activity is poorly understood. TRPM7 kinase phosphorylates serines (Ser) and threonines (Thr) located within alpha-helices. A few in vitro substrates have been identified so far, but whether they serve as native substrates remains elusive. The present project gives insight into the involvement of TRPM7 in allergic reactions, the pathogenesis of acute-graft-versus-host disease (GVHD) and more generally pro-inflammatory responses possibly contributing to the identification of novel pharmacological targets for these pathological conditions.
Deletion of the ubiquitously expressed Trpm7 is embryonic lethal. Deletion of the Trpm7 kinase domain also leads to early embryonic lethality, most likely due to reduced channel function in this mutant. However, heterozygous mice are viable and develop severe hypomagnesaemia upon Mg2+ restriction, leading to increased mortality, susceptibility to seizures as well as prevalence for allergic hypersensitivity. Interestingly, mice with genetic inactivation of TRPM7 kinase activity by a point mutation within the active site of the kinase (K1646R, TRPM7KI) show no obvious phenotype. However, in a more careful analysis we found that TRPM7 kinase activity regulates mast cell degranulation and histamine release, highlighting the role of the TRPM7 kinase in the hyper-allergic phenotype observed previously. The paper entitled ‘TRPM7 kinase activity regulates murine mast cell degranulation’ has been published earlier this year in the Journal of Physiology.
Tissue-specific deletion of Trpm7 in the T cell lineage disrupts thymopoiesis, and results in altered chemokine and cytokine expression profiles, indicating that TRPM7 channel and/or kinase are important for T cell function. A kinase-deficient TRPM7KI mouse model revealed an essential role for TRPM7 kinase activity in intra-epithelial T cell homeostasis. A manuscript entitled: ‘The kinase activity of the TRPM7 channel-enzyme is essential for gut colonization by T cells and graft-versus-host reaction’ has been submitted to Immunity. Importantly, the project revealed an essential role of the TRPM7 kinase activity in gut colonization by alloreactive T cells in an acute graft-versus-host-disease model. Therefore, TRPM7 kinase activity is crucial in T cell function, suggesting a therapeutic potential of kinase inhibitors in averting acute graft-versus-host-disease.
The involvement of TRPM7 in the pathogenesis of dis-regulated immune responses highlights the necessity for novel pharmacological tools. A better understanding of physiological TRPM7 regulation and its impact on Mg2+ and immune system homeostasis will yield crucial insight into body homeostasis and in vivo activation mechanisms. Epidemiological relevance of pro-inflammatory diseases in modern societies is such that the discovery of therapeutic targets is a major priority in health research. The achievement of the proposed objectives will affect technological innovation, knowledge about human physiology and likely allow transforming basic science into clinical practice. The envisaged end point of the research in this project is translational to establish new strategies for the treatment of pro-inflammatory diseases, such as acute graft-versus-host-disease or autoimmune diseases, such as multiple sclerosis.
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