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

Siller, A.; Hofer, N. T.; Tomagra, G.; Wiederspohn, N.; Hess, S.; Benkert, J.; Gaifullina, A.; Spaich, D.; Duda, J.; Poetschke, C.; Vilusic, K.; Fritz, E. M.; Schneider, T.; Kloppenburg, P.; Liss, B.; Carabelli, V.; Carbone, E.; Ortner, N. J.; Striessnig, J.

doi:10.1101/2021.02.10.430224

bioRxiv · 10.1101/2021.02.10.430224

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

Siller, A.·Hofer, N. T.·Tomagra, G.·Wiederspohn, N.·Hess, S.·Benkert, J.·Gaifullina, A.·Spaich, D.·Duda, J.·Poetschke, C.·Vilusic, K.·Fritz, E. M.·Schneider, T.·Kloppenburg, P.·Liss, B.·Carabelli, V.·Carbone, E.·Ortner, N. J.·Striessnig, J.

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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 Parkinsons 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 {beta}2-splice variants {beta}2a and {beta}2e stabilize Cav2.3 gating properties allowing sustained Cav2.3 availability during simulated pacemaking and enhanced Ca2+-currents during bursts. We confirmed the expression of {beta}2a and {beta}2e-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 {beta}2a- or {beta}2e-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 {beta}-subunit alternative splicing for Cav2.3 Ca2+-signaling in highly vulnerable SN DA neurons.

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Siller, A., Hofer, N. T., Tomagra, G., Wiederspohn, N., Hess, S., Benkert, J., Gaifullina, A., Spaich, D., Duda, J., Poetschke, C., Vilusic, K., Fritz, E. M., Schneider, T., Kloppenburg, P., Liss, B., Carabelli, V., Carbone, E., Ortner, N. J., Striessnig, J.. 2021-02-10. Alternative splicing of auxiliary β2-subunits stabilizes Cav2.3 Ca2+ channel activity in continuously active midbrain dopamine neurons. https://doi.org/10.1101/2021.02.10.430224

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