The palmitoyl acyltransferase ZDHHC14 controls Kv1-family potassium channel clustering at the axon initial segment

  1. Shaun S Sanders  Is a corresponding author
  2. Luiselys M Hernandez
  3. Heun Soh
  4. Santi Karnam
  5. Randall S Walikonis
  6. Anastasios V Tzingounis
  7. Gareth M Thomas  Is a corresponding author
  1. University of Guelph, Canada
  2. Temple University School of Medicine, United States
  3. University of Connecticut, United States

Abstract

The palmitoyl acyltransferase (PAT) ZDHHC14 is highly expressed in the hippocampus and is the only PAT predicted to bind Type I PDZ domain-containing proteins. However, ZDHHC14's neuronal roles are unknown. Here, we identify the PDZ domain-containing Membrane-associated Guanylate Kinase (MaGUK) PSD93 as a direct ZDHHC14 interactor and substrate. PSD93, but not other MaGUKs, localizes to the Axon Initial Segment (AIS). Using lentiviral-mediated shRNA knockdown in rat hippocampal neurons, we find that ZDHHC14 controls palmitoylation and AIS clustering of PSD93 and also of Kv1 potassium channels, which directly bind PSD93. Neurodevelopmental expression of ZDHHC14 mirrors that of PSD93 and Kv1 channels and, consistent with ZDHHC14's importance for Kv1 channel clustering, loss of ZDHHC14 decreases outward currents and increases action potential firing in hippocampal neurons. To our knowledge, these findings identify the first neuronal roles and substrates for ZDHHC14 and reveal a previously unappreciated role for palmitoylation in control of neuronal excitability.

Data availability

All data generated during this study are included in the manuscript and supporting files. Source data files have been provided for all figures in the source data excel file.

Article and author information

Author details

  1. Shaun S Sanders

    Molecular and Cellular Biology, University of Guelph, Guelph, Canada
    For correspondence
    ssande03@uoguelph.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9661-141X
  2. Luiselys M Hernandez

    Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Heun Soh

    Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Santi Karnam

    Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Randall S Walikonis

    Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Anastasios V Tzingounis

    Physiology and Neurobiology, University of Connecticut, Storrs, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4605-3437
  7. Gareth M Thomas

    Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, United States
    For correspondence
    gareth.thomas@temple.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3183-8431

Funding

Brody Family Medical Trust Fund Fellowship

  • Shaun S Sanders

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#4939) of Temple University.

Reviewing Editor

  1. Leon D Islas, Universidad Nacional Autónoma de México, Mexico

Publication history

  1. Received: February 14, 2020
  2. Accepted: November 12, 2020
  3. Accepted Manuscript published: November 13, 2020 (version 1)
  4. Version of Record published: November 24, 2020 (version 2)

Copyright

© 2020, Sanders et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Shaun S Sanders
  2. Luiselys M Hernandez
  3. Heun Soh
  4. Santi Karnam
  5. Randall S Walikonis
  6. Anastasios V Tzingounis
  7. Gareth M Thomas
(2020)
The palmitoyl acyltransferase ZDHHC14 controls Kv1-family potassium channel clustering at the axon initial segment
eLife 9:e56058.
https://doi.org/10.7554/eLife.56058
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