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, Desirée Spaich, Johanna Duda, Christina Poetschke, Kristina Vilusic, Eva Fritz, Toni Schneider, Peter Kloppenburg, Birgit Liss, Valentina Carabelli, Emilio Carbone, Nadine J. Ortner, Jörg Striessnig
Abstract
In dopaminergic (DA) Substantia nigra (SN) neurons Cav2.3 R-type Ca 2+ -currents contribute to somatodendritic Ca 2+ -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 Ca 2+ -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 Ca 2+ -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 Ca 2+ signals contributing to the (patho)physiological role of Cav2.3 channels in PD.