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Dominant-negative calcium channel suppression by truncated constructs involves a kinase implicated in the unfolded protein response.

ABSTRACT: Expression of the calcium channel Ca(V)2.2 is markedly suppressed by coexpression with truncated constructs of Ca(V)2.2. Furthermore, a two-domain construct of Ca(V)2.1 mimicking an episodic ataxia-2 mutation strongly inhibited Ca(V)2.1 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(V)2 calcium channel family, there is no cross-suppression between Ca(V)2 and Ca(V)3 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(V)2.2, together with full-length Ca(V)2.2, reduced the level not only of Ca(V)2.2 protein but also the coexpressed alpha2delta-2. Thapsigargin, which globally activates the unfolded protein response, very markedly suppressed Ca(V)2.2 currents and also reduced the expression level of both Ca(V)2.2 and alpha2delta-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.

SUBMITTER: Page KM

PROVIDER: S-EPMC6729303 | biostudies-literature | 2004 Jun

REPOSITORIES: biostudies-literature

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Dominant-negative calcium channel suppression by truncated constructs involves a kinase implicated in the unfolded protein response.

Page Karen M KM Heblich Fay F Davies Anthony A Butcher Adrian J AJ Leroy Jerôme J Bertaso Federica F Pratt Wendy S WS Dolphin Annette C AC

The Journal of neuroscience : the official journal of the Society for Neuroscience 20040601 23

Expression of the calcium channel Ca(V)2.2 is markedly suppressed by coexpression with truncated constructs of Ca(V)2.2. Furthermore, a two-domain construct of Ca(V)2.1 mimicking an episodic ataxia-2 mutation strongly inhibited Ca(V)2.1 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 re ...[more]

PMID: 15190113

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Dataset Information

Dominant-negative calcium channel suppression by truncated constructs involves a kinase implicated in the unfolded protein response.

Publications

Dominant-negative calcium channel suppression by truncated constructs involves a kinase implicated in the unfolded protein response.

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