Origins, roles and mechanisms of ion selectivity for voltage-gated sodium and calcium channels

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The electrical signals which control bodily functions are shaped by ion flux through highly ion selective voltage-gated channels. Our current understanding of how ion channels are ion selective is understood by Roderick Mackinnon's Nobel Prize winning X-ray crystal structure of the potassium-selective channel. Ion selectivity in potassium channels involves the narrowest point of the hourglass shaped ion selective pore where there are critical ion selectivity filter residues. The work of the Spafford lab shows that the ion selectivity model proposed for potassium channels, doesn't equally apply for eukaryotic sodium or calcium channels. The Spafford lab has discovered the only mechanism where nature generates ion channels with alternative sodium and calcium selective pores, and these ion channels provide unique insights into the regulation of sodium and calcium selectivity. We propose experiments to explore NALCN (NA Leak ChaNnel) and Cav3 T-type channel, respectively which possess alternatively spliced exons that transforms NALCN and T-type channels into calcium- or sodium-selective channels. This work is momentous as it demonstrates that ion selectivity can be generated with and without the canonical ion selectivity filter. The simplicity of non-vertebrates models provides a unique perspective in understanding how ionic signalling is adapted for differing body plans. We will evaluate for example, how Nav1 channels and their beta subunits are adapted for rapid, efficient electrical communication and patterning within the developing nervous systems lacking vertebrate ankyrin and glial dependent signalling; how sodium-selective T-type channels can functionally replace Nav1 channels in the invertebrate heart, and how T-type channels are universally regulated by calcium sensor, calmodulin. Our analyses extends to basal single cell eukaryote, Salpingoeca rosetta. The single cell eukaryote perspective alters our interpretation of what these ion channels are for, as sodium and calcium channels have only been considered to date in the context of animals with nervous systems. The Spafford lab's research provide a non-traditional perspective in the analyses of voltage-gated sodium and calcium channels from basal, single cell ancestors to invertebrates. Results to date have provided insights that are largely anti-dogmatic, in an ion channel field dominated by perspectives derived from a narrow window of physiological studies in vertebrates or from bacterial channel structures.