Insights into the molecular foundations of electrical excitation.

This is the era of the brain. Developing a deep understanding of the inner workings of this exceptionally complex organ and using that knowledge to invent new ways to affect its function is the premier scientific challenge of this century [1]. The fundamental currency of the brain and nervous system are electrical signals that orchestrate millisecond signaling through the networks of neurons that drive thought, feeling, and action. These rapid signals arise from a special class of transmembrane proteins called ion channels that control the transit of small ions across the cell membrane in response to diverse cues including changes in voltage, pressure, temperature, neurotransmitter binding, and intracellular signals [2,3]. Advances in the ability to interrogate ion channel molecular mechanisms have brought this field, once dominated by functional studies, to a level in which the full suite of structural, biophysical, and computational approaches can be used in concert with functional studies to dissect molecular mechanism [4,5]. This special issue of the Journal of Molecular Biology collects an exciting set of reviews and original research contributions that brings a slice of this fascinating field to the attention of readers. Structural studies define the architectural underpinnings that are crucial for uncovering how channels function. As ion channels are complex allosteric proteins with many moving parts, defining atomic scale structures of ion channels, ion channel subunits, and ion channel modulators is at the heart and cutting edge of channel studies. Five of the reviews in this issue detail some of the exciting developments in structural studies of different classes of cation channels, which include the main drivers of neuronal electrical signals. Payandeh and Minor analyze the exceptional recent advances in structural studies of bacterial voltage-gated sodium channels, BacNaVs, and how these are shaping our understanding of their related eukaryotic voltagegated sodium and calcium channel cousins [6]. Van Petegem covers advances in the structural understanding of the one of the largest characterized ion channels, the ryanodine receptor, and underscores the importance of integrated structural approaches for dissecting this intracellular calcium channel [7]. Kellenberger and Grutter describe structural and mechanistic advances in our understanding of two related channel types that share a common architecture in the face of little primary sequence similarly: