Chronic ethanol exposure induces an N‐type calcium channel splice variant with altered channel kinetics

Abstract

Chronic ethanol exposure increases the density of Ntype calcium channels in brain. We report that ethanol increases levels of mRNA for a splice variant of the N channel specific subunit a 1 2.2 that lacks exon 31a. Whole cell recordings demonstrated an increase in N-type current with a faster activation rate and a shift in activation to more negative potentials after chronic alcohol exposure, consistent with increased abundance of channels containing this variant. These results identify a novel mechanism whereby chronic ethanol exposure can increase neuronal excitability by altering levels of channel splice variants.

A Blocker of N- and T-type Voltage-Gated Calcium Channels Attenuates Ethanol-Induced Intoxication, Place Preference, Self-Administration, and Reinstatement

“…We have shown previously that acute ethanol exposure inhibits N-type calcium channels (Solem et al, 1997), and chronic ethanol exposure increases N-type channel function and density (McMahon et al, 2000; Newton et al, 2005). Low voltage-activated T-type calcium channels are biophysically distinct from N-type channels and contribute to rhythmic firing and bursting behaviors related to processes such as sleep and epileptiform activity (Huguenard, 1996).…”

Increase in Expression of α1 and α2/δ1 Subunits of L-Type High Voltage-Gated Calcium Channels After Sustained Ethanol Exposure in Cerebral Cortical Neurons

“…That is, N-type HVCCs as well as L-type of HVCCs are up-regulated by chronic ethanol treatment of PC12 cells (4,38) and of striatal synaptosomes from rats (39). This modification of the channels is reported to be due to changing channel kinetics such as fastening activation of the channels (40). Such difference in behaviors of L-and N-type HVCCs to chronic ethanol treatment between these reports and our results may be due to the differences in both cell types used in each experiment and ethanol concentrations exposed, although the exact reasons for such difference are not clear at present.…”

BK Channels: mediators and models for alcohol tolerance

“…Alternative splicing is a powerful mechanism for regulating gene expression, contributing to the functional diversity of proteins [67], and enabling cells to adapt to various environmental cues. Particularly relevant to this review are recent studies on mRNAs encoding N-type calcium channels in PC12 cells [68] and in vivo rat glutamate receptor NMDAR1(N- methyl d -aspartic acid receptor 1) subunit [69] demonstrating that alternative splicing can be modulated by alcohol and that alternatively spliced isoforms can differ in their alcohol sensitivity. BK channel alternative splicing has been extensively characterized [13].…”