@article {Page5400, author = {Karen M. Page and Fay Heblich and Anthony Davies and Adrian J. Butcher and Jer{\^o}me Leroy and Federica Bertaso and Wendy S. Pratt and Annette C. Dolphin}, title = {Dominant-Negative Calcium Channel Suppression by Truncated Constructs Involves a Kinase Implicated in the Unfolded Protein Response}, volume = {24}, number = {23}, pages = {5400--5409}, year = {2004}, doi = {10.1523/JNEUROSCI.0553-04.2004}, publisher = {Society for Neuroscience}, abstract = {Expression of the calcium channel CaV2.2 is markedly suppressed by coexpression with truncated constructs of CaV2.2. Furthermore, a two-domain construct of CaV2.1 mimicking an episodic ataxia-2 mutation strongly inhibited CaV2.1 currents. We have now determined the specificity of this effect, identified a potential mechanism, and have shown that such constructs also inhibit endogenous calcium currents when transfected into neuronal cell lines. Suppression of calcium channel expression requires interaction between truncated and full-length channels, because there is inter-subfamily specificity. Although there is marked cross-suppression within the CaV2 calcium channel family, there is no cross-suppression between CaV2 and CaV3 channels. The mechanism involves activation of a component of the unfolded protein response, the endoplasmic reticulum resident RNA-dependent kinase (PERK), because it is inhibited by expression of dominant-negative constructs of this kinase. Activation of PERK has been shown previously to cause translational arrest, which has the potential to result in a generalized effect on protein synthesis. In agreement with this, coexpression of the truncated domain I of CaV2.2, together with full-length CaV2.2, reduced the level not only of CaV2.2 protein but also the coexpressed α2δ-2. Thapsigargin, which globally activates the unfolded protein response, very markedly suppressed CaV2.2 currents and also reduced the expression level of both CaV2.2 and α2δ-2 protein. We propose that voltage-gated calcium channels represent a class of difficult-to-fold transmembrane proteins, in this case misfolding is induced by interaction with a truncated cognate CaV channel. This may represent a mechanism of pathology in episodic ataxia-2.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/24/23/5400}, eprint = {https://www.jneurosci.org/content/24/23/5400.full.pdf}, journal = {Journal of Neuroscience} }