SUMOylation of NaV1.2 channels regulates the velocity of backpropagating action potentials in cortical pyramidal neurons

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Abstract

Voltage-gated sodium channels located in axon initial segments (AIS) trigger action potentials (AP) and play pivotal roles in the excitability of cortical pyramidal neurons. The differential electrophysiological properties and distributions of Na_V1.2 and Na_V1.6 channels lead to distinct contributions to AP initiation and propagation. While Na_V1.6 at the distal AIS promotes AP initiation and forward propagation, Na_V1.2 at the proximal AIS promotes the backpropagation of APs to the soma. Here, we show the Small Ubiquitin-like Modifier (SUMO) pathway modulates Na⁺ channels at the AIS to increase neuronal gain and the speed of backpropagation. Since SUMO does not affect Na_V1.6, these effects were attributed to SUMOylation of Na_V1.2. Moreover, SUMO effects were absent in a mouse engineered to express Na_V1.2-Lys38Gln channels that lack the site for SUMO linkage. Thus, SUMOylation of Na_V1.2 exclusively controls I_NaP generation and AP backpropagation, thereby playing a prominent role in synaptic integration and plasticity.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file; the Source Data files will be uploaded to the Dryad server promptly

The following data sets were generated

1. Fleidervish I
2. Kotler O
3. Khrapunsky Y
4. Shvartsman A
5. Dai H
6. Plant L
7. Goldstein S
(2023) SUMOylation of NaV1.2 channels regulates the velocity of backpropagating action potentials in cortical pyramidal neurons
Dryad Digital Repository, doi:10.5061/dryad.tx95x6b1g.

https://dx.doi.org/10.5061/dryad.tx95x6b1g

Article and author information

Author details

Oron Kotler

Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel

Competing interests
The authors declare that no competing interests exist.
Yana Khrapunsky

Depatrment of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel

Competing interests
The authors declare that no competing interests exist.
Arik Shvartsman

Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel

Competing interests
The authors declare that no competing interests exist.
Hui Dai

Department of Pediatrics, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.
Leigh D Plant

Department of Pharmaceutical Sciences, Northeastern University, Boston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1622-1655
Steven AN Goldstein

Department of Pediatrics, University of California, Irvine, Irvine, United States

For correspondence
sgoldst2@hs.uci.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5207-5061
Ilya Fleidervish

Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel

For correspondence
ilya@bgu.ac.il

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5501-726X

Funding

Israel Science Foundation (1384/19)

Ilya Fleidervish

National Institutes of Health (R01HL10549)

Steven AN Goldstein

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 carried out at the Ben-Gurion University of the Negev in accordance with the recommendations of guidelines for the welfare of experimental animals. Animal experiments were approved by the Institutional Animal Care and Use Committee of Ben-Gurion University (protocols IL-68-09-2019(A), IL-79-10-2020(D)).

Copyright

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.