Stabilization of negative activation voltages of Cav1.3 L-Type Ca2+-channels by alternative splicing.

Stabilization of negative activation voltages of Cav1.3 L-Type Ca2+-channels by alternative splicing. Channels (Austin). 2021 Dec;15(1):38-52 Authors: Hofer NT, Pinggera A, Nikonishyna YV, Tuluc P, Fritz EM, Obermair GJ, Striessnig J Abstract -->Low voltage-activated Cav1.3 L-type Ca2+-channels are key regulators of neuronal excitability controlling neuronal development and different types of learning and memory. Their physiological functions are enabled by their negative activation voltage-range, which allows Cav1.3 to be active at subthreshold voltages. Alternative splicing in the C-terminus of their pore-forming α1-subunits gives rise to C-terminal long (Cav1.3L) and short (Cav1.3S) splice variants allowing Cav1.3S to activate at even more negative voltages than Cav1.3L. We discovered that inclusion of exons 8b, 11, and 32 in Cav1.3S further shifts activation (-3 to -4 mV) and inactivation (-4 to -6 mV) to more negative voltages as revealed by functional characterization in tsA-201 cells. We found transcripts of these exons in mouse chromaffin cells, the cochlea, and the brain. Our data further suggest that Cav1.3-containing exons 11 and 32 constitute a significant part of native channels in the brain. We therefore investigated the effect of these splice variants on human disease variants. Splicing did not prevent the gating defects of the previously reported human pathogenic variant S652L, which further shifted the voltage...
Source: Channels - Category: Molecular Biology Tags: Channels (Austin) Source Type: research