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TRPM7 kinase mediates hypomagnesemia-induced seizure-related death
Man Liu1, Hong Liu1, Feng Feng1
1Cardiovascular Division, Department of Medicine, The Lillehei Heart Institute, University of Minnesota at Twin Cities, 2231 6th Street SE, CCRB 4-141, Minneapolis, MN, 55455, USA.
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.
Insights
Low magnesium (Hypomagnesemia) can cause seizures and death. TRPM7 kinase activity contributes to these Hypomagnesemia-induced seizures and deaths, with inhibition reducing inflammation and oxidative stress.
Area of Science:
- Neuroscience
- Molecular Biology
- Physiology
Background:
- Hypomagnesemia (HypoMg) is linked to seizures and mortality, but underlying mechanisms remain unclear.
- Transient receptor potential cation channel subfamily M 7 (TRPM7) possesses both Mg transport and kinase functions, implicating it in cellular Mg homeostasis.
- The specific role of TRPM7's kinase function in HypoMg-related neurological complications requires elucidation.
Purpose of the Study:
- To investigate the contribution of TRPM7 kinase activity to HypoMg-induced seizures and mortality.
- To determine if inhibiting TRPM7 kinase function can mitigate HypoMg-induced neurological deficits.
- To explore sex-based differences in HypoMg-induced inflammation and oxidative stress.
Main Methods:
- Utilized wild-type and TRPM7 kinase-dead (TRPM7K1646R) mice fed a HypoMg diet for six weeks.
- Monitored serum Mg levels, brain TRPM7 expression, seizure incidence, and mortality rates.
- Assessed brain inflammation and oxidative stress markers, particularly in the hippocampus, with a focus on sex differences.
Main Results:
- HypoMg mice exhibited decreased serum Mg, elevated brain TRPM7, and significant mortality, with females being more susceptible.
- Deaths were preceded by seizures; TRPM7K1646R mice demonstrated resistance to seizure-induced death.
- TRPM7 kinase inhibition suppressed HypoMg-induced brain inflammation and oxidative stress, which were more pronounced in female mice.
Conclusions:
- TRPM7 kinase activity is a key factor in HypoMg-induced seizures and mortality.
- Inhibiting TRPM7 kinase function offers a potential therapeutic strategy to reduce HypoMg-related neurological damage.
- Sex-specific differences in hippocampal inflammation and oxidative stress highlight the complex interplay between HypoMg, TRPM7, and sex in neurological outcomes.
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