Cav1.2 I-II linker structure and Timothy syndrome

Lior Almagor, Orna Chomsky-Hecht, Adva Ben-Mocha, Doran Hendin-Barak, Nathan Dascal, Joel A. Hirsch

Research output: Contribution to journalArticlepeer-review

Abstract

Cav channels are multi-subunit protein complexes that enable inward cellular Ca2+ 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 CaV1.2 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 CaV1.2 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.

Original languageEnglish
Pages (from-to)468-472
Number of pages5
JournalChannels
Volume6
Issue number6
DOIs
StatePublished - 2012

Keywords

  • Timothy syndrome
  • Voltage-dependent calcium channels
  • Voltage-dependent inactivation
  • α-helix

Fingerprint

Dive into the research topics of 'Cav1.2 I-II linker structure and Timothy syndrome'. Together they form a unique fingerprint.

Cite this