title: Molecular Interactions in the Voltage Sensor Controlling Gating Properties of CaV Calcium Channels.
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.
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria; Department of Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria. Electronic address: petronel.tuluc@uibk.ac.at.
authors.forename: Petronel
authors.initials: P
authors.lastname: Tuluc
authors.affiliation: Department of Physiology and Membrane Biology, UC Davis, Davis, CA 95616, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
authors.forename: Bruno
authors.initials: B
authors.lastname: Benedetti
authors.affiliation: Department of Physiology and Medical Physics, Medical University Innsbruck, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria. Electronic address: bernhard.e.flucher@i-med.ac.at.
authors.forename: Bernhard E
authors.initials: BE
authors.lastname: Flucher
mesh_terms: D017398:Alternative Splicing; D001120:Arginine / Q000378:metabolism; D001224:Aspartic Acid / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011487:Protein Conformation
chemical_list: D020746:Calcium Channels, L-Type; D001224:Aspartic Acid; D001120:Arginine
keywords: Ca(V); calcium channel; voltage gating; voltage-sensing domain