Role of the chanzyme TRPM7 in the nervous system in health and disease

The channel kinase (chanzyme) transient receptor potential melastatin-like 7 (TRPM7) has a unique dual protein structure composed of an ion channel with an alpha-kinase domain on its C-terminus. In the nervous system, under physiological conditions, TRPM7 contributes to critical neurobiological processes ranging from synaptic transmission to cognitive functions. Following certain pathological triggers, TRPM7 mediates neurotoxicity, neuro-injuries, and neuronal death. Here, we summarize the current knowledge of TRPM7 functions in neuronal systems in health and disease. The molecular mechanisms by which this chanzyme might regulate synaptic and cognitive functions are discussed. We also discuss the lack of knowledge regarding the molecular mechanisms responsible for turning TRPM7 into "a vicious tool" that mediates neuronal death following certain pathological triggers. Some synthetic and natural pharmacological modulators of the TRPM7 channel and its alpha-kinase are reviewed. We suggest that based on current knowledge, we should reshape our thinking regarding the implications of TRPM7 in neurological and neurodegenerative disorders. Moreover, we propose a paradigm shift concerning the targeting of TRPM7 as a therapeutic approach for treating certain neurological diseases. We agree that TRPM7 overexpression or overactivation may mediate neurodegenerative processes following certain triggers. However, TRPM7 dysfunction and/or downregulation might also be among the pathological changes leading to neurodegeneration. Consequently, further investigations are required before we decide whether blocking or activating the chanzyme is the correct therapeutic approach to treat certain neurological and/or neurodegenerative diseases.