A Destructive Interaction Mechanism Accounts for Dominant-Negative Effects of Misfolded Mutants of Voltage-Gated Calcium Channels

• Published in: The Journal of neuroscience Vol. 28; no. 17; pp. 4501 - 4511
• Main Authors: Mezghrani, Alexandre, Monteil, Arnaud, Watschinger, Katrin, Sinnegger-Brauns, Martina J, Barrere, Christian, Bourinet, Emmanuel, Nargeot, Joel, Striessnig, Jorg, Lory, Philippe
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 23.04.2008; Society for Neuroscience
• Subjects: Amino Acid Substitution - genetics; Calcium Channel Blockers - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channels - chemistry; Calcium Channels - genetics; Calcium Channels - metabolism; Calcium Channels, N-Type - chemistry; Calcium Channels, N-Type - genetics; Calcium Channels, N-Type - metabolism; Cell Line; Cell Line, Tumor; Cerebellar Ataxia - genetics; Cerebellar Ataxia - metabolism; Humans; Protein Folding; Sequence Deletion
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.2844-07.2008

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.