Low-Mg^sup 2+^ treatment increases sensitivity of voltage-gated Na+ channels to Ca^sup 2+^/calmodulin-mediated modulation in cultured hippocampal neurons

Culture of hippocampal neurons in low-Mg... medium (low-Mg... neurons) results in induction of continuous seizure activity. However, the underlying mechanism of the contribution of low Mg... to hyperexcitability of neurons has not been clarified. Our data, obtained using the patch-clamp technique, s...

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Published inAmerican Journal of Physiology: Cell Physiology Vol. 308; no. 8; p. C594
Main Authors Guo, Feng, Zhou, Pei-Dong, Gao, Qing-Hua, Gong, Jian, Feng, Rui, Xu, Xiao-Xue, Liu, Shu-Yuan, Hu, Hui-Yuan, Zhao, Mei-Mi, Adam, Hogan-Cann, Cai, Ji-Qun, Hao, Li-Ying
Format Journal Article
LanguageEnglish
Published Bethesda American Physiological Society 15.04.2015
Subjects
Binding sites
Convulsions & seizures
Magnesium
Mutation
Neurons
Neuropsychology
Physiology
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Summary:Culture of hippocampal neurons in low-Mg... medium (low-Mg... neurons) results in induction of continuous seizure activity. However, the underlying mechanism of the contribution of low Mg... to hyperexcitability of neurons has not been clarified. Our data, obtained using the patch-clamp technique, show that voltage-gated Na... channel (VGSC) activity, which is associated with a persistent, noninactivating Na... current (I...), was modulated by calmodulin (CaM) in a concentration-dependent manner in normal and low-Mg... neurons, but the channel activity was more sensitive to Ca.../CaM regulation in low-Mg... than normal neurons. The increased sensitivity of VGSCs in low-Mg... neurons was partially retained when CaM... and CaM..., CaM mutants with disabled binding sites in the N or C lobe, were used but was diminished when CaM..., a CaM mutant in which all four Ca... sites are disabled, was used, indicating that functional Ca...-binding sites from either lobe of CaM are required for modulation of VGSCs in low-Mg... neurons. Furthermore, the number of neurons exhibiting colocalization of CaM with the VGSC subtypes Na...1.1, Na...1.2, and Na...1.3 was significantly higher in low- Mg... than normal neurons, as shown by immunofluorescence. Our main finding is that low-Mg... treatment increases sensitivity of VGSCs to Ca.../CaM-mediated regulation. Our data reveal that CaM, as a core regulating factor, connects the functional roles of the three main intracellular ions, Na..., Ca..., and Mg..., by modulating VGSCs and provides a possible explanation for the seizure discharge observed in low-Mg... neurons. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0363-6143
1522-1563