The selectivity of voltage-gated sodium channels for lithium ions is determined by strong electrostatic interactions between the ion pathway through the channel and hydrated ions, and hydration water exchanges within the ion pathway, according to a study by researchers at Wakayama Medical University. The results provide a foundation for using lithium-ion permeability as a molecular basis for new drugs targeting neurological disorders.
Voltage-gated sodium channels are membrane proteins that open up in response to membrane depolarization. Once opened, the channels conduct sodium ions inward to initiate and propagate electrical signals in excitable cells such as neurons, cardiomyocytes, and skeletal muscle fibers. The high selectivity of the protein channels for sodium ion is well known. However, they also conduct lithium ions with similar efficiency. Although the physiological role is not fully understood, lithium has been used to treat multiple neurological disorders.
In a new study published in the Journal of General Physiology, researchers at Wakayama Medical University investigated the molecular basis for the lithium-ion selectivity of voltage-gated sodium channels. Using electrophysiology and x-ray crystallography, the researchers studied the relationship between channel structure and lithium-ion permeability.
In the study, Katsumasa Irie and co-workers show that lithium permeability cannot be explained simply by ionic size or charge alone. Instead, the data suggests that subtle differences in ion–protein interactions within the channel’s selectivity filter shape the energetic landscape of permeation. Lithium’s smaller ionic radius and stronger hydration energy appear to alter how it sheds water molecules and coordinates with the channel’s selectivity filter residues. These differences influence both conduction efficiency and the stability of conductive states.
Using Dynaflow Resolve, the researchers were able to perform detailed electrophysiologic analysis of channel function, providing greater insight into how channel ion–protein interactions affect lithium-ion permeability than what has previously been possible. Specifically, the fast solution exchange enabled by the Dynaflow Resolve system made it possible for the researchers to obtain kinetic insight into rapid transitions in channel activity. By improving temporal precision and experimental control, the authors were able to reduce ambiguity around how quickly ions enter and exit the pore, demonstrating a more complex channel response than previously appreciated.
Katsumasa Irie and co-workers suggest that the expanded insight into the mechanisms by which lithium ions enter cells can deepen the understanding of the biological role played by lithium and that it may lead to improved treatments for various neurological disorders.
We congratulate the researchers on their achievements and are proud and happy that they have chosen to use Dynaflow Resolve in their research.
Read the article Structure-function analysis of the lithium-ion selectivity of the voltage-gated sodium channel on Journal of General Physiology’s website.