학술논문
β2-subunit alternative splicing stabilizes Cav2.3 Ca2+ channel activity during continuous midbrain dopamine neuron-like activity.
Document Type
Article
Author
Siller, Anita; Hofer, Nadja T.; Tomagra, Giulia; Burkert, Nicole; Hess, Simon; Benkert, Julia; Gaifullina, Aisylu; Spaich, Desiree; Duda, Johanna; Poetschke, Christina; Vilusic, Kristina; Fritz, Eva Maria; Schneider, Toni; Kloppenburg, Peter; Liss, Birgit; Carabelli, Valentina; Carbone, Emilio; Ortner, Nadine Jasmin; Striessnig, Jörg
Source
Subject
*ALTERNATIVE RNA splicing
*DOPAMINERGIC neurons
*MESENCEPHALON
*SUBSTANTIA nigra
*PARKINSON'S disease
*DOPAMINE
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Language
ISSN
2050-084X
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. [ABSTRACT FROM AUTHOR]