A destructive interaction mechanism accounts for dominant-negative effects of misfolded mutants of voltage-gated calcium channels.
Channelopathies are often linked to defective protein folding and trafficking. Among them, the calcium channelopathy episodic ataxia type-2 (EA2) is an autosomal dominant disorder related to mutations in the pore-forming Ca(v)2.1 subunit of P/Q-type calcium channels. Although EA2 is linked to loss of Ca(v)2.1 channel activity, the molecular mechanism underlying dominant inheritance remains unclear. Here, we show that EA2 mutants as well as a truncated form (D(I-II)) of the Ca(v)3.2 subunit of T-type calcium channel are misfolded, retained in the endoplasmic reticulum, and subject to proteasomal degradation. Pulse-chase experiments revealed that misfolded mutants bind to nascent wild-type Ca(v) subunits and induce their subsequent degradation, thereby abolishing channel activity. We conclude that this destructive interaction mechanism promoted by Ca(v) mutants is likely to occur in EA2 and in other inherited dominant channelopathies.
Mezghrani
Alexandre
A
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Institut de Génomique Fonctionnelle, Institut National de la Santé et de la Recherche Médicale, 34094 Montpellier, France. alexandre.mezghrani@igf.cnrs.fr
Monteil
Arnaud
A
Watschinger
Katrin
K
Sinnegger-Brauns
Martina J
MJ
Barrère
Christian
C
Bourinet
Emmanuel
E
Nargeot
Joël
J
Striessnig
Jörg
J
Lory
Philippe
P
D019943:Amino Acid Substitution / Q000235:genetics*; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002524:Cerebellar Ataxia / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017510:Protein Folding; D017384:Sequence Deletion
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020864:Calcium Channels, N-Type