Referenced in: none

Automatically associated channels: Nav1.1 , Nav1.2 , Nav1.3

Title: Low-Mg(2+) treatment increases sensitivity of voltage-gated Na(+) channels to Ca(2+)/calmodulin-mediated modulation in cultured hippocampal neurons.

Authors: Feng Guo, Pei-Dong Zhou, Qing-hua Gao, Jian Gong, Rui Feng, Xiao-Xue Xu, Shu-yuan Liu, Hui-Yuan Hu, Mei-mi Zhao, Hogan-Cann Adam, Ji-Qun Cai, Li-Ying Hao

Journal, date & volume: Am. J. Physiol., Cell Physiol., 2015 Apr 15 , 308, C594-605

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25652447

Abstract
Culture of hippocampal neurons in low-Mg(2+) medium (low-Mg(2+) neurons) results in induction of continuous seizure activity. However, the underlying mechanism of the contribution of low Mg(2+) 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 (INa,P), was modulated by calmodulin (CaM) in a concentration-dependent manner in normal and low-Mg(2+) neurons, but the channel activity was more sensitive to Ca(2+)/CaM regulation in low-Mg(2+) than normal neurons. The increased sensitivity of VGSCs in low-Mg(2+) neurons was partially retained when CaM12 and CaM34, CaM mutants with disabled binding sites in the N or C lobe, were used but was diminished when CaM1234, a CaM mutant in which all four Ca(2+) sites are disabled, was used, indicating that functional Ca(2+)-binding sites from either lobe of CaM are required for modulation of VGSCs in low-Mg(2+) neurons. Furthermore, the number of neurons exhibiting colocalization of CaM with the VGSC subtypes NaV1.1, NaV1.2, and NaV1.3 was significantly higher in low- Mg(2+) than normal neurons, as shown by immunofluorescence. Our main finding is that low-Mg(2+) treatment increases sensitivity of VGSCs to Ca(2+)/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(2+), and Mg(2+), by modulating VGSCs and provides a possible explanation for the seizure discharge observed in low-Mg(2+) neurons.