Mining Protein Evolution for Insights into Mechanisms of Voltage-Dependent Sodium Channel Auxiliary Subunits

Handbook of Experimental Pharmacology
Steven MolinaroloChristopher A Ahern

Abstract

Voltage-gated sodium channel (VGSC) beta (β) subunits have been called the "overachieving" auxiliary ion channel subunit. Indeed, these subunits regulate the trafficking of the sodium channel complex at the plasma membrane and simultaneously tune the voltage-dependent properties of the pore-forming alpha-subunit. It is now known that VGSC β-subunits are capable of similar modulation of multiple isoforms of related voltage-gated potassium channels, suggesting that their abilities extend into the broader voltage-gated channels. The gene family for these single transmembrane immunoglobulin beta-fold proteins extends well beyond the traditional VGSC β1-β4 subunit designation, with deep roots into the cell adhesion protein family and myelin-related proteins - where inherited mutations result in a myriad of electrical signaling disorders. Yet, very little is known about how VGSC β-subunits support protein trafficking pathways, the basis for their modulation of voltage-dependent gating, and, ultimately, their role in shaping neuronal excitability. An evolutionary approach can be useful in yielding new clues to such functions as it provides an unbiased assessment of protein residues, folds, and functions. An approach is described here ...Continue Reading

Citations

Jul 8, 2020·Biomolecules·Samantha C SalvageAntony P Jackson
Jul 24, 2018·Frontiers in Physiology·Claire H FeethamRichard Barrett-Jolley
Aug 7, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Fernando Villa-DiazThomas Scior
Oct 17, 2019·Biomolecules·Eric CortadaMarcel Verges

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