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Alternative splicing tunes sodium channels to support channel- and neuron-specific effects

Gabriele Lignani, Andrianos Liavas, Dimitri M Kullmann, Stephanie Schorge
doi: https://doi.org/10.1101/2020.09.30.320788
Gabriele Lignani
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
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Andrianos Liavas
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
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Dimitri M Kullmann
1Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
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Stephanie Schorge
2Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK
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  • For correspondence: s.schorge@ucl.ac.uk
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Abstract

Neuronal excitability is tightly regulated, requiring rapidly activating and inactivating voltage-gated sodium channels to allow accurate temporal encoding of information. Alternative splicing greatly broadens the repertoire of channels, but the adaptive significance of this phenomenon is incompletely understood. An alternative splicing event that is conserved across vertebrates affects part of the first domain of sodium channels and modulates their availability after inactivation. Here we use this conserved splicing event to ask whether this modulation has consistent effects in different neuronal backgrounds, or whether a conserved splicing event can be exploited to produce distinct effects in different cell types. We show that the consequences of alternate splicing of human Nav1.1 and Nav1.2 for neuronal activity depend on whether they are expressed in the cell types where they normally predominate (interneurons or excitatory neurons, respectively). Splicing in the ‘adult’ isoform in both channels is sufficient to slow action potential rise times in all neurons. However, changes to both action potential half width and maximal firing rate are specific to cell type and channel, with each channel appearing tuned to mediate effects in its predominant neuronal background. Finally, we use dynamic clamp to demonstrate that alternative splicing in Nav1.1 changes how interneurons fire during epileptiform events. Our data show that, for sodium channels, despite conserved amino acid changes and similar effects on channel gating, alternative splicing has distinct impacts on neuronal properties, thus highlighting how closely sodium channels are tuned to distinct cellular backgrounds.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflicts of interest: None

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 01, 2020.
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Alternative splicing tunes sodium channels to support channel- and neuron-specific effects
Gabriele Lignani, Andrianos Liavas, Dimitri M Kullmann, Stephanie Schorge
bioRxiv 2020.09.30.320788; doi: https://doi.org/10.1101/2020.09.30.320788
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Alternative splicing tunes sodium channels to support channel- and neuron-specific effects
Gabriele Lignani, Andrianos Liavas, Dimitri M Kullmann, Stephanie Schorge
bioRxiv 2020.09.30.320788; doi: https://doi.org/10.1101/2020.09.30.320788

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