title: Cell-type-specific tuning of Cav1.3 Ca(2+)-channels by a C-terminal automodulatory domain.
abstract: Cav1.3 L-type Ca(2+)-channel function is regulated by a C-terminal automodulatory domain (CTM). It affects channel binding of calmodulin and thereby tunes channel activity by interfering with Ca(2+)- and voltage-dependent gating. Alternative splicing generates short C-terminal channel variants lacking the CTM resulting in enhanced Ca(2+)-dependent inactivation and stronger voltage-sensitivity upon heterologous expression. However, the role of this modulatory domain for channel function in its native environment is unkown. To determine its functional significance in vivo, we interrupted the CTM with a hemagglutinin tag in mutant mice (Cav1.3DCRD(HA/HA)). Using these mice we provide biochemical evidence for the existence of long (CTM-containing) and short (CTM-deficient) Cav1.3 α1-subunits in brain. The long (HA-labeled) Cav1.3 isoform was present in all ribbon synapses of cochlear inner hair cells. CTM-elimination impaired Ca(2+)-dependent inactivation of Ca(2+)-currents in hair cells but increased it in chromaffin cells, resulting in hyperpolarized resting potentials and reduced pacemaking. CTM disruption did not affect hearing thresholds. We show that the modulatory function of the CTM is affected by its native environment in different cells and thus occurs in a cell-type specific manner in vivo. It stabilizes gating properties of Cav1.3 channels required for normal electrical excitability.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck Innsbruck, Austria.
authors.forename: Anja
authors.initials: A
authors.lastname: Scharinger
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Saarland University Homburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Eckrich
authors.affiliation: Laboratory of Cellular and Molecular Neuroscience, Department of Drug Science, Nanostructured Interfaces and Surfaces Center, University of Torino Torino, Italy.
authors.forename: David H
authors.initials: DH
authors.lastname: Vandael
authors.affiliation: Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University Mannheim, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Schönig
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck Innsbruck, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Koschak
authors.affiliation: Department of Otorhinolaryngology, Saarland University Homburg, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Hecker
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck Innsbruck, Austria.
authors.forename: Gurjot
authors.initials: G
authors.lastname: Kaur
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Iowa City, IA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck Innsbruck, Austria.
authors.forename: Anupam
authors.initials: A
authors.lastname: Sah
authors.affiliation: Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University Mannheim, Germany.
authors.forename: Dusan
authors.initials: D
authors.lastname: Bartsch
authors.affiliation: Department of Physiology and Medical Physics, Innsbruck Medical University Innsbruck, Austria.
authors.forename: Bruno
authors.initials: B
authors.lastname: Benedetti
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lieb
authors.affiliation: Department of Otorhinolaryngology, Saarland University Homburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schick
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck Innsbruck, Austria.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck Innsbruck, Austria.
authors.forename: Martina J
authors.initials: MJ
authors.lastname: Sinnegger-Brauns
authors.affiliation: Laboratory of Cellular and Molecular Neuroscience, Department of Drug Science, Nanostructured Interfaces and Surfaces Center, University of Torino Torino, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Carbone
authors.affiliation: Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, Saarland University Homburg, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Engel
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences, University of Innsbruck Innsbruck, Austria.
authors.forename: Jörg
authors.initials: J
authors.lastname: Striessnig
keywords: alternative splicing; calcium channels; channel gating; chromaffin cells; hair cell; hearing