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The Journal of Neuroscience, June 9, 2004, 24(23):5400-5409; doi:10.1523/JNEUROSCI.0553-04.2004

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Cellular/Molecular
Dominant-Negative Calcium Channel Suppression by Truncated Constructs Involves a Kinase Implicated in the Unfolded Protein Response

Karen M. Page, ^* Fay Heblich, ^* Anthony Davies, ^* Adrian J. Butcher, ^* Jerôme Leroy, Federica Bertaso, Wendy S. Pratt, and Annette C. Dolphin

Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom

Expression of the calcium channel Ca_V2.2 is markedly suppressed by coexpression with truncated constructs of Ca_V2.2. Furthermore, a two-domain construct of Ca_V2.1 mimicking an episodic ataxia-2 mutation strongly inhibited Ca_V2.1 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 Ca_V2 calcium channel family, there is no cross-suppression between Ca_V2 and Ca_V3 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 Ca_V2.2, together with full-length Ca_V2.2, reduced the level not only of Ca_V2.2 protein but also the coexpressed 2-2. Thapsigargin, which globally activates the unfolded protein response, very markedly suppressed Ca_V2.2 currents and also reduced the expression level of both Ca_V2.2 and 2-2 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 Ca_V channel. This may represent a mechanism of pathology in episodic ataxia-2.

Key words: calcium channel; current; suppression; episodic ataxia-2; truncation; aggregation

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Received Feb 17, 2004; revised May 3, 2004; accepted May 3, 2004.

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