Molecular Interactions in the Voltage Sensor Controlling Gating Properties of CaV Calcium Channels

Petronel Tuluc, Vladimir Yarov-Yarovoy, Bruno Benedetti, Bernhard E. Flucher

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Voltage-gated calcium channels (CaV) regulate numerous vital functions in nerve and muscle cells. To fulfill their diverse functions, the multiple members of the CaV channel family are activated over a wide range of voltages. Voltage sensing in potassium and sodium channels involves the sequential transition of positively charged amino acids across a ring of residues comprising the charge transfer center. In CaV channels, the precise molecular mechanism underlying voltage sensing remains elusive. Here we combined Rosetta structural modeling with site-directed mutagenesis to identify the molecular mechanism responsible for the specific gating properties of two CaV1.1 splice variants. Our data reveal previously unnoticed interactions of S4 arginines with an aspartate (D1196) outside the charge transfer center of the fourth voltage-sensing domain that are regulated by alternative splicing of the S3-S4 linker. These interactions facilitate the final transition into the activated state and critically determine the voltage sensitivity and current amplitude of these CaV channels. Voltage-gated calcium channels (CaV) translate membrane depolarization into calcium influx that regulates muscle contraction, hormone secretion, or synaptic transmission. Using computational structural modeling, site-directed mutagenesis, and electrophysiology, Tuluc et al. identified the mechanism responsible for the different voltage sensitivities of two CaV1.1 calcium channel splice variants.

Original languageEnglish (US)
JournalStructure
DOIs
StateAccepted/In press - May 28 2015

Keywords

  • Ca
  • Calcium channel
  • Voltage gating
  • Voltage-sensing domain

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

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