A destructive interaction mechanism accounts for dominant-negative effects of misfolded mutants of voltage-gated calcium channels.

Abstract

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.

• Authors: Alexandre Mezghrani, Arnaud Monteil, Katrin Watschinger, Martina J Sinnegger-Brauns, Christian Barrère, Emmanuel Bourinet, Joël Nargeot, Jörg Striessnig, Philippe Lory
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 28 Issue 17 Pg. 4501-11 (Apr 23 2008) ISSN: 1529-2401 [Electronic] United States
• PMID: 18434528 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Calcium Channels
• Calcium Channels, N-Type
• voltage-dependent calcium channel (P-Q type)

Topics

• Amino Acid Substitution (genetics)
• Calcium Channel Blockers (metabolism, pharmacology)
• Calcium Channels (chemistry, genetics, metabolism)
• Calcium Channels, N-Type (chemistry, genetics, metabolism)
• Cell Line
• Cell Line, Tumor
• Cerebellar Ataxia (genetics, metabolism)
• Humans
• Protein Folding
• Sequence Deletion