Voltage-gated sodium channels (VGSCs) are a group of ion channels which are responsible for initiation and propagation of action potential in excitable cells. VGSCs are also involved in many physiological activities and are suggested for treatment of several disorders like neuropathic pain or cardiac dysfunction. Despite the importance of these channels, limited structural data are available and lots of questions remain to be addressed. In this study, we investigate permeation of sodium ions in mammalian VGSCs and provide new results on the channel structure and function.
The first crystal structure of a bacterial VGSC was determined in 2011. It has triggered many attempts to investigate properties of mammalian VGSCs. However, the bacterial VGSCs are considerably different from mammalian ones, which make homology modeling considerably more complicated. In a previous study, we have constructed a promising model for the mammalian Nav1.4 channel and validated this model using functional studies from binding of mu-conotoxin GIIIA. Our results are consistent with available experimental data from mutations and binding constant of GIIIA.
In this study, we investigate permeation of sodium ions through the proposed Nav1.4 model, which is based on the more recent VGSC crystal structure. From analysis of trajectory data from long MD simulations, we find the binding sites of sodium ions in the model. We then calculate PMFs for sodium ions to study the permeation mechanism. Our results provide mechanistic explanations for permeation and selectivity of sodium ions through mammalian VGSCs.