Journal article
Mining Protein Evolution for Insights into Mechanisms of Voltage-Dependent Sodium Channel Auxiliary Subunits
Handbook of experimental pharmacology, Vol.246, pp.33-49
2018
DOI: 10.1007/164_2017_75
PMID: 29464397
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 which indicates the greater emergence of the modern β-subunits roughly 400 million years ago in the early neurons of Bilateria and bony fish, and the unexpected presence of distant homologues in bacteriophages. Recent structural breakthroughs containing α and β eukaryotic sodium channels containing subunits suggest a novel role for a highly conserved polar contact that occurs within the transmembrane segments. Overall, a mixture of approaches will ultimately advance our understanding of the mechanism for β-subunit interactions with voltage-sensor containing ion channels and membrane proteins.
Details
- Title: Subtitle
- Mining Protein Evolution for Insights into Mechanisms of Voltage-Dependent Sodium Channel Auxiliary Subunits
- Creators
- Steven Molinarolo - Department of Molecular Physiology and Biophysics, Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USADaniele Granata - Institute for Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, PA, USAVincenzo Carnevale - Institute for Computational Molecular Science, College of Science and Technology, Temple University, Philadelphia, PA, USA. vincenzo.carnevale@temple.eduChristopher A Ahern - Department of Molecular Physiology and Biophysics, Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA. christopher-ahern@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Handbook of experimental pharmacology, Vol.246, pp.33-49
- Publisher
- Germany
- DOI
- 10.1007/164_2017_75
- PMID
- 29464397
- eISBN
- 3319902849; 9783319902845
- ISSN
- 0171-2004
- eISSN
- 1865-0325
- Grant note
- R01 GM122420 / NIGMS NIH HHS
- Language
- English
- Date published
- 2018
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984070104102771
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