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J Neurosci
2004 Jun 09;2423:5400-9. doi: 10.1523/JNEUROSCI.0553-04.2004.
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Dominant-negative calcium channel suppression by truncated constructs involves a kinase implicated in the unfolded protein response.
Page KM
,
Heblich F
,
Davies A
,
Butcher AJ
,
Leroy J
,
Bertaso F
,
Pratt WS
,
Dolphin AC
.
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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.
Ahern,
Intramembrane charge movements and excitation- contraction coupling expressed by two-domain fragments of the Ca2+ channel.
2001, Pubmed
Ahern,
Intramembrane charge movements and excitation- contraction coupling expressed by two-domain fragments of the Ca2+ channel.
2001,
Pubmed
Arikkath,
Molecular characterization of a two-domain form of the neuronal voltage-gated P/Q-type calcium channel alpha(1)2.1 subunit.
2002,
Pubmed
Barclay,
Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells.
2001,
Pubmed
,
Xenbase
Brodbeck,
The ducky mutation in Cacna2d2 results in altered Purkinje cell morphology and is associated with the expression of a truncated alpha 2 delta-2 protein with abnormal function.
2002,
Pubmed
,
Xenbase
Burgess,
Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse.
1997,
Pubmed
Campbell,
Voltage-dependent calcium channel beta-subunits in combination with alpha 1 subunits, have a GTPase activating effect to promote the hydrolysis of GTP by G alpha o in rat frontal cortex.
1995,
Pubmed
Cantí,
Evidence for two concentration-dependent processes for beta-subunit effects on alpha1B calcium channels.
2001,
Pubmed
,
Xenbase
Cantí,
Identification of residues in the N terminus of alpha1B critical for inhibition of the voltage-dependent calcium channel by Gbeta gamma.
1999,
Pubmed
,
Xenbase
Catterall,
Structure and regulation of voltage-gated Ca2+ channels.
2000,
Pubmed
Chemin,
Neuronal T-type alpha 1H calcium channels induce neuritogenesis and expression of high-voltage-activated calcium channels in the NG108-15 cell line.
2002,
Pubmed
Cormack,
FACS-optimized mutants of the green fluorescent protein (GFP).
1996,
Pubmed
Denier,
High prevalence of CACNA1A truncations and broader clinical spectrum in episodic ataxia type 2.
1999,
Pubmed
Dreyfuss,
Messenger-RNA-binding proteins and the messages they carry.
2002,
Pubmed
Ertel,
Nomenclature of voltage-gated calcium channels.
2000,
Pubmed
Fletcher,
Dystonia and cerebellar atrophy in Cacna1a null mice lacking P/Q calcium channel activity.
2001,
Pubmed
Hans,
Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels.
1999,
Pubmed
Harding,
Transcriptional and translational control in the Mammalian unfolded protein response.
2002,
Pubmed
Harding,
Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase.
1999,
Pubmed
Harding,
Perk is essential for translational regulation and cell survival during the unfolded protein response.
2000,
Pubmed
Horwich,
Protein aggregation in disease: a role for folding intermediates forming specific multimeric interactions.
2002,
Pubmed
Imai,
An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin.
2001,
Pubmed
Jouvenceau,
Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel.
2001,
Pubmed
Jun,
Ablation of P/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(1A)-subunit.
1999,
Pubmed
Liu,
The unfolded protein response.
2003,
Pubmed
Mazumder,
Translational control by the 3'-UTR: the ends specify the means.
2003,
Pubmed
Meir,
Calcium channel beta subunit promotes voltage-dependent modulation of alpha 1 B by G beta gamma.
2000,
Pubmed
Mori,
Tripartite management of unfolded proteins in the endoplasmic reticulum.
2000,
Pubmed
Moss,
The novel product of a five-exon stargazin-related gene abolishes Ca(V)2.2 calcium channel expression.
2002,
Pubmed
,
Xenbase
Okagaki,
The maternal transcript for truncated voltage-dependent Ca2+ channels in the ascidian embryo: a potential suppressive role in Ca2+ channel expression.
2001,
Pubmed
,
Xenbase
Ophoff,
Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.
1996,
Pubmed
Pestova,
Molecular mechanisms of translation initiation in eukaryotes.
2001,
Pubmed
Pfaffl,
Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR.
2002,
Pubmed
Plummer,
Alternative splicing of the sodium channel SCN8A predicts a truncated two-domain protein in fetal brain and non-neuronal cells.
1997,
Pubmed
Raghib,
Dominant-negative synthesis suppression of voltage-gated calcium channel Cav2.2 induced by truncated constructs.
2001,
Pubmed
Robbins,
On the mechanism of M-current inhibition by muscarinic m1 receptors in DNA-transfected rodent neuroblastoma x glioma cells.
1993,
Pubmed
Ron,
Translational control in the endoplasmic reticulum stress response.
2002,
Pubmed
Rutkowski,
A trip to the ER: coping with stress.
2004,
Pubmed
Ryu,
Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease.
2002,
Pubmed
Sachs,
Eukaryotic translation initiation: there are (at least) two sides to every story.
2000,
Pubmed
Schorge,
Calcium channel activation stabilizes a neuronal calcium channel mRNA.
1999,
Pubmed
Subramony,
Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits.
2003,
Pubmed
Tinker,
Regions responsible for the assembly of inwardly rectifying potassium channels.
1996,
Pubmed
,
Xenbase
Tomlinson,
Functional properties of a neuronal class C L-type calcium channel.
1993,
Pubmed
,
Xenbase
Usowicz,
Differential expression by nerve growth factor of two types of Ca2+ channels in rat phaeochromocytoma cell lines.
1990,
Pubmed
Wappl,
Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia.
2002,
Pubmed
,
Xenbase
Wielowieyski,
Alternative splicing in intracellular loop connecting domains II and III of the alpha 1 subunit of Cav1.2 Ca2+ channels predicts two-domain polypeptides with unique C-terminal tails.
2001,
Pubmed
