β2-subunit alternative splicing stabilizes Cav2.3 Ca2+ channel activity during continuous midbrain dopamine neuron-like activity
- University of Innsbruck, Austria
- University of Torino, Italy
- University of Ulm, Germany
- University of Cologne, Germany
Abstract
In dopaminergic (DA) substantia nigra (SN) neurons Cav2.3 R-type Ca2+-currents contribute to somatodendritic Ca2+-oscillations. This activity 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. Here we show that in tsA-201-cells the membrane-anchored β2-splice variants β2a and β2e are required to 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-subunit transcripts in the mouse SN and in identified SN DA neurons. Patch-clamp recordings of mouse DA midbrain neurons in culture and SN DA neurons in brain slices revealed SNX-482-sensitive R-type Ca2+-currents with voltage-dependent gating properties that suggest modulation by β2a- and/or β2e-subunits. Thus, β-subunit alternative splicing may prevent a fraction of Cav2.3 channels from inactivation in continuously active, highly vulnerable SN DA neurons, thereby also supporting Ca2+ signals contributing to the (patho)physiological role of Cav2.3 channels in PD.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Raw data have been provided for mean population data shown in Figures and Tables.
Article and author information
Author details
Funding
Austrian Science Fund (P27809,P35722,CavX-DOC 30 doc.fund)
- Jörg Striessnig
Tyrolean Science Fund (UNI-0404/2345)
- Nadine Jasmin Ortner
Italian Miur (2015FNWP34)
- Emilio Carbone
Compagnia di San Paolo (CSTO165284)
- Emilio Carbone
Austrian Science Fund (P35087)
- Nadine Jasmin Ortner
Hamburg Institute for Advanced Study (Research Fellowship)
- Birgit Liss
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments and procedures were performed in strict accordance with the European Community's Council Directive 2010/63/UE and approved by the Italian Ministry of Health and the Local Organism responsible for animal welfare at the University of Torino (authorization DGSAF 0011710-P-26/07/2017) and the local authorities at the University of Ulm (Regierungspräsidium Tübingen, Ref: 35/9185.81-3; Reg. Nr. o.147) and University of Cologne (LANUV NRW, Recklinghausen, Germany (84-02.05.20.12.254).
Reviewing Editor
- Henry M Colecraft, Columbia University, United States
Publication history
- Preprint posted: February 10, 2021 (view preprint)
- Received: February 11, 2021
- Accepted: July 4, 2022
- Accepted Manuscript published: July 6, 2022 (version 1)
- Accepted Manuscript updated: July 8, 2022 (version 2)
- Version of Record published: July 22, 2022 (version 3)
- Version of Record updated: July 27, 2022 (version 4)
Copyright
© 2022, Siller 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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β2-subunit alternative splicing stabilizes Cav2.3 Ca2+ channel activity during continuous midbrain dopamine neuron-like activity
eLife 11:e67464.
https://doi.org/10.7554/eLife.67464
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