Ca(V)1.2 I-II linker structure and Timothy syndrome

Channels (Austin). 2012 Nov-Dec;6(6):468-72. doi: 10.4161/chan.22078. Epub 2012 Sep 18.


Ca(V) channels are multi-subunit protein complexes that enable inward cellular Ca(2+) currents in response to membrane depolarization. We recently described structure-function studies of the intracellular α1 subunit domain I-II linker, directly downstream of domain IS6. The results show the extent of the linker's helical structure to be subfamily dependent, as dictated by highly conserved primary sequence differences. Moreover, the difference in structure confers different biophysical properties, particularly the extent and kinetics of voltage and calcium-dependent inactivation. Timothy syndrome is a human genetic disorder due to mutations in the Ca(V)1.2 gene. Here, we explored whether perturbation of the I-II linker helical structure might provide a mechanistic explanation for a Timothy syndrome mutant's (human Ca(V)1.2 G406R equivalent) biophysical effects on inactivation and activation. The results are equivocal, suggesting that a full mechanistic explanation for this Timothy syndrome mutation requires further investigation.

MeSH terms

  • Animals
  • Autistic Disorder
  • Calcium Channels, L-Type / chemistry*
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Humans
  • Ion Channel Gating
  • Long QT Syndrome / genetics
  • Long QT Syndrome / metabolism*
  • Long QT Syndrome / physiopathology
  • Mutation / genetics
  • Protein Structure, Secondary
  • Structure-Activity Relationship
  • Syndactyly / genetics
  • Syndactyly / metabolism*
  • Syndactyly / physiopathology
  • Xenopus


  • Calcium Channels, L-Type
  • L-type calcium channel alpha(1C)

Supplementary concepts

  • Timothy syndrome