β2-subunit alternative splicing stabilizes Cav2.3 Ca2+ channel activity during continuous midbrain dopamine neuron-like activity
Anita Siller,
Nadja T Hofer,
Giulia Tomagra,
Nicole Burkert,
Simon Hess,
Julia Benkert,
Aisylu Gaifullina,
Desiree Spaich,
Johanna Duda,
Christina Poetschke,
Kristina Vilusic,
Eva Maria Fritz,
Toni Schneider,
Peter Kloppenburg,
Birgit Liss,
Valentina Carabelli,
Emilio Carbone,
Nadine Jasmin Ortner,
Jörg Striessnig
Affiliations
Anita Siller
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
Nadja T Hofer
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
Giulia Tomagra
Department of Drug Science, NIS Centre, University of Torino, Torino, Italy
Nicole Burkert
Institute of Applied Physiology, University of Ulm, Ulm, Germany, Ulm, Germany
Simon Hess
Institute for Zoology, Biocenter, University of Cologne, Cologne, Germany
Julia Benkert
Institute of Applied Physiology, University of Ulm, Ulm, Germany, Ulm, Germany
Aisylu Gaifullina
Institute of Applied Physiology, University of Ulm, Ulm, Germany, Ulm, Germany
Desiree Spaich
Institute of Applied Physiology, University of Ulm, Ulm, Germany, Ulm, Germany
Johanna Duda
Institute of Applied Physiology, University of Ulm, Ulm, Germany, Ulm, Germany
Christina Poetschke
Institute of Applied Physiology, University of Ulm, Ulm, Germany, Ulm, Germany
Kristina Vilusic
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
Eva Maria Fritz
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
Toni Schneider
Institute of Neurophysiology, University of Cologne, Cologne, Germany
Institute for Zoology, Biocenter, University of Cologne, Cologne, Germany
Birgit Liss
Institute of Applied Physiology, University of Ulm, Ulm, Germany, Ulm, Germany; Linacre College & New College, University of Oxford, Oxford, United Kingdom
Valentina Carabelli
Department of Drug Science, NIS Centre, University of Torino, Torino, Italy
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
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.
