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In honor of SfN 2011 and the 31,000 brains who attended, here’s a revisit of the year’s top F1000-ranked (so far) article in the Neuroscience Faculty, “The crystal structure of a voltage-gated sodium channel”.

Jian Payandeh, Todd Scheuer, Ning Zheng, and William Catterall from the University of Washington, Department of Pharmacology, won high praise from nine F1000 evaluators for their report describing the unique crystal structure of a voltage-gated Na+ channel in a closed-pore conformation (Nature Jul 21). Sodium channels regulate various physiological activities, and inherited diseases including genetic epilepsy have been associated with mutations in the voltage-gated sodium channel. The authors’ work determining its 3D architecture contributes enormously to understanding the basis for electrical signaling in excitable cells – such as neurons – and the action of drugs used for pain, epilepsy, and cardiac arrhythmia at the atomic level.

With an F1000 Article Factor (FFa) of 32, it’s also the third highest ranked neuroscience paper since F1000 Biology launched in 2001. F1000 evaluators variously declared the UW team’s work “a crowning achievement,” a “landmark,” a “major and long-sought-after breakthrough in the ion channel field,” and “a seminal work for neurobiology and a drumbeat for structural membrane biology.”

This first-ever 3D model, built from the bacterium Arcobacter butzleri, reveals useful similarities between the sodium channel and the calcium channel. But it also reveals unique hydrophobic features of the sodium channel that could be implicit in the effectiveness of local anesthetics and other hydrophobic molecules. The research answered many questions, but also raised several, including, as noted by the Nature editors at the time of publication, how the structure’s S4 segment moves, how the channel selects sodium over potassium ions, and the function of fenestrations featured in this crystal structure but not in potassium channels.

University of Calgary schizophrenia researcher Gerald Zamponi whose lab studies various aspects of neuronal voltage-dependent calcium channels, sums up the study this way:

The authors expressed a bacterial sodium channel gene in an insect cell line to generate enough protein to obtain crystals for high-throughput X-ray diffraction. By doing so, [they] managed to get a ~2.7 angstrom resolution image of a tetrameric sodium channel in its closed conformation with the voltage sensors already in the open conformation. Based on this work, the authors have gained unparalleled insights into sodium channel structure and function. Absolutely beautiful!

Medicinal chemists Dmitri Coultin and Manoj Desai at Gilead Sciences call this research

one of the most important breakthroughs in the history of research on voltage-gated ion channels and may have direct impact on cardiovascular and CNS pharmacology and other drug-discovery research.

Still, there is work to be done. How hydrophobic molecules enter and exit the closed sodium channels remains a mystery. Research into this important question is an obvious next step that should shed light on how local anesthetics interact with the channel.