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Role of enzyme-coupled TRP channels in immune cell function

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Cation channels in immune cell homeostasis

Signalling pathways regulated by the melastatin-like transient receptor potential cation channel-kinase (TRPM7) play crucial roles in leukocyte physiology. Therefore, it is important to identify whether TRPM7 represents a potential target for immune therapy.

Fundamental Research
Health

The melastatin-like transient-receptor-potential (TRP) cation channel subfamily (TRPM) belongs to the mammalian TRP channel superfamily and comprises the dual-function protein TRPM7. A divalent-selective cation channel, conducting mainly Mg2+, Ca2+ and Zn2+, TRPM7 has a functional, non-redundant, c-terminal kinase domain. TRPM7 has been implicated in immune cell function as well as in cell survival, proliferation, apoptosis and migration. The TRPM7 kinase moiety phosphorylates serine and threonine residues. Some in vitro substrates have been identified, but whether they are native substrates is still unknown. The EU-funded RETIF (Role of enzyme-coupled TRP channels in immune cell function) project studied the involvement of TRPM7 in pro-inflammatory and allergic responses to identify novel pharmacological targets for these pathological conditions. Using different mouse models, researchers showed that the deletion of the ubiquitously expressed TRPM7 or even the kinase domain is embryonic lethal. However, heterozygous kinase-deficient mice are viable but develop severe hypomagnesaemia, leading to increased mortality and allergic hypersensitivity. Curiously, mice with inactivation of TRPM7 kinase activity by a point mutation within the active site of the kinase showed no obvious phenotype. However, in their experiments, researchers found that TRPM7 kinase regulates mast cell degranulation and histamine release, highlighting the role of TRPM7 kinase in the hyper-allergic phenotype. Mouse models with tissue-specific knockouts demonstrated that deletion of Trpm7 in the T cell lineage disrupts thymopoiesis and alters chemokine and cytokine expression profiles, indicating that TRPM7 is important for T cell function. A kinase-deficient mouse model proved an essential role for TRPM7 kinase in intra-epithelial T cell homeostasis and gut colonisation by T cells. Importantly, the project revealed an essential role of the TRPM7 kinase in an acute graft-versus-host-disease model. Discovery of new therapeutic targets for pro-inflammatory diseases is a major priority in biomedical research. Understanding the physiological regulation of TRPM7 and its impact on Mg2+ and immune system homeostasis yields important insights into whole body homeostasis. RETIF outcomes should help translate new strategies for the treatment of pro-inflammatory and autoimmune diseases.

Keywords

TRPM7, cation channel, alpha-kinase domain, RETIF, graft-versus-host-disease model

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