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Alternative splicing of auxiliary β2-subunits stabilizes Cav2.3 Ca2+ channel activity in continuously active midbrain dopamine neurons

Anita Siller, View ORCID ProfileNadja T. Hofer, View ORCID ProfileGiulia Tomagra, Nicole Wiederspohn, View ORCID ProfileSimon Hess, Julia Benkert, Aisylu Gaifullina, Desiree Spaich, Johanna Duda, Christina Pötschke, Kristina Vilusic, View ORCID ProfileEva Maria Fritz, View ORCID ProfileToni Schneider, View ORCID ProfilePeter Kloppenburg, View ORCID ProfileBirgit Liss, View ORCID ProfileValentina Carabelli, View ORCID ProfileEmilio Carbone, View ORCID ProfileNadine J. Ortner, View ORCID ProfileJörg Striessnig
doi: https://doi.org/10.1101/2021.02.10.430224
Anita Siller
1Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
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Nadja T. Hofer
1Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
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Giulia Tomagra
3Department of Drug Science, NIS Centre, University of Torino, Torino, Italy
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Nicole Wiederspohn
4Institute of Applied Physiology, University of Ulm, Ulm, Germany
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Simon Hess
5Institute for Zoology, Biocenter, CECAD, University of Cologne, Cologne, Germany
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Julia Benkert
4Institute of Applied Physiology, University of Ulm, Ulm, Germany
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Aisylu Gaifullina
4Institute of Applied Physiology, University of Ulm, Ulm, Germany
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Desiree Spaich
4Institute of Applied Physiology, University of Ulm, Ulm, Germany
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Johanna Duda
4Institute of Applied Physiology, University of Ulm, Ulm, Germany
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Christina Pötschke
4Institute of Applied Physiology, University of Ulm, Ulm, Germany
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Kristina Vilusic
1Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
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Eva Maria Fritz
1Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
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Toni Schneider
2Institute of Neurophysiology, University of Cologne, Cologne, Germany
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Peter Kloppenburg
5Institute for Zoology, Biocenter, CECAD, University of Cologne, Cologne, Germany
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Birgit Liss
4Institute of Applied Physiology, University of Ulm, Ulm, Germany
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Valentina Carabelli
3Department of Drug Science, NIS Centre, University of Torino, Torino, Italy
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  • ORCID record for Valentina Carabelli
Emilio Carbone
3Department of Drug Science, NIS Centre, University of Torino, Torino, Italy
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Nadine J. Ortner
1Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
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  • For correspondence: nadine.ortner@uibk.ac.at joerg.striessnig@uibk.ac.at
Jörg Striessnig
1Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
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  • For correspondence: nadine.ortner@uibk.ac.at joerg.striessnig@uibk.ac.at
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Abstract

In dopaminergic (DA) substantia nigra (SN) neurons Cav2.3 R-type Ca2+-currents contribute to somatodendritic Ca2+-oscillations. These may contribute to the selective degeneration of these neurons in Parkinson’s disease (PD) since Cav2.3-knockout is neuroprotective in a PD mouse model. However, the typical Cav2.3 gating would predict complete channel inactivation during SN DA neuronal firing. Here we show that in tsA-201-cells the membrane-anchored β2-splice variants β2a and β2e stabilize Cav2.3 gating properties allowing sustained Cav2.3 availability during simulated pacemaking and enhanced Ca2+-currents during bursts. We confirmed the expression of β2a and β2e-subunits in the SN and identified SN DA neurons. Patch-clamp recordings of SN DA neurons in mouse brain slices revealed R-type Ca2+-currents similar to β2a- or β2e-stabilized Cav2.3-currents and recordings in cultured murine DA neurons confirmed their activity during pacemaking. Taken together, our data support an important (patho)physiological role of β-subunit alternative splicing for Cav2.3 Ca2+-signaling in highly vulnerable SN DA neurons.

Competing Interest Statement

The authors have declared no competing interest.

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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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Alternative splicing of auxiliary β2-subunits stabilizes Cav2.3 Ca2+ channel activity in continuously active midbrain dopamine neurons
Anita Siller, Nadja T. Hofer, Giulia Tomagra, Nicole Wiederspohn, Simon Hess, Julia Benkert, Aisylu Gaifullina, Desiree Spaich, Johanna Duda, Christina Pötschke, Kristina Vilusic, Eva Maria Fritz, Toni Schneider, Peter Kloppenburg, Birgit Liss, Valentina Carabelli, Emilio Carbone, Nadine J. Ortner, Jörg Striessnig
bioRxiv 2021.02.10.430224; doi: https://doi.org/10.1101/2021.02.10.430224
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Alternative splicing of auxiliary β2-subunits stabilizes Cav2.3 Ca2+ channel activity in continuously active midbrain dopamine neurons
Anita Siller, Nadja T. Hofer, Giulia Tomagra, Nicole Wiederspohn, Simon Hess, Julia Benkert, Aisylu Gaifullina, Desiree Spaich, Johanna Duda, Christina Pötschke, Kristina Vilusic, Eva Maria Fritz, Toni Schneider, Peter Kloppenburg, Birgit Liss, Valentina Carabelli, Emilio Carbone, Nadine J. Ortner, Jörg Striessnig
bioRxiv 2021.02.10.430224; doi: https://doi.org/10.1101/2021.02.10.430224

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