Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

The sodium leak channel complex is modulated by voltage and extracellular calcium

Han Chow Chua, Matthias Wulf, Claudia Weidling, Lise Pilgaard Rasmussen, Stephan Alexander Pless
doi: https://doi.org/10.1101/740456
Han Chow Chua
Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthias Wulf
Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Claudia Weidling
Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lise Pilgaard Rasmussen
Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephan Alexander Pless
Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: stephan.pless@sund.ku.dk
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Summary

The sodium leak channel (NALCN) is essential for survival in mammals: NALCN mutations are life-threatening in humans and knockout is lethal in mice. However, the basic functional and pharmacological properties of NALCN have remained elusive. Here, we found that the robust function of NALCN in heterologous systems requires co-expression of UNC79, UNC80 and FAM155A. The resulting NALCN channel complex is constitutively active, conducts monovalent cations but is blocked by physiological concentrations of extracellular divalent cations. Our data support the notion that NALCN is directly responsible for the increased excitability observed in a variety of neurons in reduced extracellular Ca2+. Despite the smaller number of voltage-sensing residues in the putative voltage sensors of NALCN, the channel complex shows voltage-dependent modulation of the constitutive current, suggesting that voltage-sensing domains can give rise to a broader range of gating phenotypes than previously anticipated. Our work points towards formerly unknown contributions of NALCN to neuronal excitability and opens avenues for pharmacological targeting.

Highlights

  • Function of NALCN requires UNC79, UNC80 and FAM155A

  • The complex is permeable to monovalent cations, but is blocked by divalent cations

  • The complex displays a constitutively active, voltage-modulated current phenotype

  • Positively charged side chains in S4 of NALCN VSD I and II confer voltage sensitivity

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted August 20, 2019.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
The sodium leak channel complex is modulated by voltage and extracellular calcium
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
The sodium leak channel complex is modulated by voltage and extracellular calcium
Han Chow Chua, Matthias Wulf, Claudia Weidling, Lise Pilgaard Rasmussen, Stephan Alexander Pless
bioRxiv 740456; doi: https://doi.org/10.1101/740456
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
The sodium leak channel complex is modulated by voltage and extracellular calcium
Han Chow Chua, Matthias Wulf, Claudia Weidling, Lise Pilgaard Rasmussen, Stephan Alexander Pless
bioRxiv 740456; doi: https://doi.org/10.1101/740456

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Neuroscience
Subject Areas
All Articles
  • Animal Behavior and Cognition (3513)
  • Biochemistry (7359)
  • Bioengineering (5338)
  • Bioinformatics (20306)
  • Biophysics (10034)
  • Cancer Biology (7763)
  • Cell Biology (11331)
  • Clinical Trials (138)
  • Developmental Biology (6444)
  • Ecology (9968)
  • Epidemiology (2065)
  • Evolutionary Biology (13346)
  • Genetics (9365)
  • Genomics (12598)
  • Immunology (7718)
  • Microbiology (19059)
  • Molecular Biology (7452)
  • Neuroscience (41106)
  • Paleontology (300)
  • Pathology (1233)
  • Pharmacology and Toxicology (2141)
  • Physiology (3171)
  • Plant Biology (6869)
  • Scientific Communication and Education (1275)
  • Synthetic Biology (1899)
  • Systems Biology (5320)
  • Zoology (1090)