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

Author:

Siller Anita,Hofer Nadja T.ORCID,Tomagra GiuliaORCID,Wiederspohn Nicole,Hess SimonORCID,Benkert Julia,Gaifullina Aisylu,Spaich Desiree,Duda Johanna,Pötschke Christina,Vilusic Kristina,Fritz Eva MariaORCID,Schneider ToniORCID,Kloppenburg PeterORCID,Liss BirgitORCID,Carabelli ValentinaORCID,Carbone EmilioORCID,Ortner Nadine J.ORCID,Striessnig JörgORCID

Abstract

AbstractIn 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 Parkinson’s 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 β2-splice variants β2a and β2e 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-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 β2a- or β2e-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 β-subunit alternative splicing for Cav2.3 Ca2+-signaling in highly vulnerable SN DA neurons.

Publisher

Cold Spring Harbor Laboratory

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