TRPM7 kinase mediates hypomagnesemia-induced seizure-related death

Abstract

Hypomagnesemia (HypoMg) can cause seizures and death, but the mechanism is unknown. Transient receptor potential cation channel subfamily M 7 (TRPM7) is a Mg transporter with both channel and kinase function. In this study, we focused on the kinase role of TRPM7 in HypoMg-induced seizures and death. Wild type C57BL/6J mice and transgenic mice with a global homozygous mutation in the TRPM7 kinase domain (TRPM7K1646R, with no kinase function) were fed with control diet or a HypoMg diet. After 6 weeks of HypoMg diet, mice had significantly decreased serum Mg, elevated brain TRPM7, and a significant rate of death, with females being most susceptible. Deaths were immediately preceded by seizure events. TRPM7K1646R mice showed resistance to seizure-induced death. HypoMg-induced brain inflammation and oxidative stress were suppressed by TRPM7K1646R. Compared to their male counterparts, HypoMg female mice had higher levels of inflammation and oxidative stress in the hippocampus. We concluded that TRPM7 kinase function contributes seizure-induced deaths in HypoMg mice and that inhibiting the kinase reduced inflammation and oxidative stress.

Beyond Ion Homeostasis: Hypomagnesemia, Transient Receptor Potential Melastatin Channel 7, Mitochondrial Function, and Inflammation

“…It seems increasingly clear that HypoMg is more than just a generalized dysfunction of Mg 2+ -dependent processes. HypoMg is a disease condition that is characterized by, among other things, increased mitochondrial dysfunction and inflammation that can lead to a type of heart failure and seizures [ 5 , 6 ].…”

“…HypoMg is related to increased inflammation [ 61 ], either caused by or resulting in mitochondrial reactive oxygen species overproduction [ 5 , 62 ], in what likely constitutes a vicious cycle. Our recent studies show that HypoMg induces inflammation [ 6 ], which leads to mitochondrial oxidative stress and cardiac diastolic dysfunction or the failure of the heart to properly relax. This lack of relaxation can progress to a unique form of heart failure: heart failure with preserved ejection fraction (HFpEF) or diastolic heart failure, which is when the heart cannot pump enough blood because it does not fill sufficiently during the relaxation phase [ 63 ].…”

“…Increased TRPM7 is associated with increased kinase signaling. Under HypoMg, the upregulation of TRPM7 can be observed, including elevated TRPM7 mRNA translation [ 80 ], protein expression [ 6 , 45 ], and TRPM7-conduced Mg 2+ currents [ 81 , 82 , 83 ]. A recent animal study on pulmonary hypertension shows an association between decreased [Mg 2+ ] i in pulmonary arterial smooth muscle cells and the upregulation of TRPM7 expression, as well as the upregulation of SLC41A1, SCL41A2, CNNM2, MRS2, and MagT1 [ 35 ].…”

“…For example, the inflammation and oxidative stress that are associated with HypoMg are correlated with TRPM7 expression and function. Our recent work shows that TRPM7 kinase activation via HypoMg contributes to the inflammation activation and oxidative stress observed in HypoMg-induced seizure activity, all of which can be significantly improved in transgenic mice with a K1646R mutation in the kinase domain that results in no kinase function while leaving transport function intact [ 6 ].…”

“…There is also a positive feedback loop between oxidative stress levels and TRPM7’s expression and function. Increased oxidative stress levels elevate TRPM7 expression and currents [ 91 , 92 ], and TRPM7 overexpression induces intracellular oxidative stress overproduction [ 6 , 93 , 94 ]. A similar positive feedback loop exists between oxidative stress and HypoMg in cardiomyocytes [ 5 , 95 ].…”