title: Functional properties of a newly identified C-terminal splice variant of Cav1.3 L-type Ca2+ channels.
abstract: An intramolecular interaction between a distal (DCRD) and a proximal regulatory domain (PCRD) within the C terminus of long Ca(v)1.3 L-type Ca(2+) channels (Ca(v)1.3(L)) is a major determinant of their voltage- and Ca(2+)-dependent gating kinetics. Removal of these regulatory domains by alternative splicing generates Ca(v)1.3(42A) channels that activate at a more negative voltage range and exhibit more pronounced Ca(2+)-dependent inactivation. Here we describe the discovery of a novel short splice variant (Ca(v)1.3(43S)) that is expressed at high levels in the brain but not in the heart. It lacks the DCRD but, in contrast to Ca(v)1.3(42A), still contains PCRD. When expressed together with α2δ1 and β3 subunits in tsA-201 cells, Ca(v)1.3(43S) also activated at more negative voltages like Ca(v)1.3(42A) but Ca(2+)-dependent inactivation was less pronounced. Single channel recordings revealed much higher channel open probabilities for both short splice variants as compared with Ca(v)1.3(L). The presence of the proximal C terminus in Ca(v)1.3(43S) channels preserved their modulation by distal C terminus-containing Ca(v)1.3- and Ca(v)1.2-derived C-terminal peptides. Removal of the C-terminal modulation by alternative splicing also induced a faster decay of Ca(2+) influx during electrical activities mimicking trains of neuronal action potentials. Our findings extend the spectrum of functionally diverse Ca(v)1.3 L-type channels produced by tissue-specific alternative splicing. This diversity may help to fine tune Ca(2+) channel signaling and, in the case of short variants lacking a functional C-terminal modulation, prevent excessive Ca(2+) accumulation during burst firing in neurons. This may be especially important in neurons that are affected by Ca(2+)-induced neurodegenerative processes.
authors: Institute of Pharmacy, Pharmacology and Toxicology and Center of Molecular Biosciences Innsbruck, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria.
authors: Gabriella
authors: G
authors: Bock
authors: Institute of Pharmacy, Pharmacology and Toxicology and Center of Molecular Biosciences Innsbruck, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria.
authors: Mathias
authors: M
authors: Gebhart
authors: Institute of Pharmacy, Pharmacology and Toxicology and Center of Molecular Biosciences Innsbruck, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria.
authors: Anja
authors: A
authors: Scharinger
authors: Department of Pharmacology and Center for Molecular Medicine, University of Cologne, Gleueler Strasse 24 and Robert-Koch-Strasse 21, D-50931 Cologne, Germany.
authors: Wanchana
authors: W
authors: Jangsangthong
authors: Institute of Pharmacy, Pharmacology and Toxicology and Center of Molecular Biosciences Innsbruck, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria.
authors: Perrine
authors: P
authors: Busquet
authors: Institute of Pharmacy, Pharmacology and Toxicology and Center of Molecular Biosciences Innsbruck, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria.
authors: Chiara
authors: C
authors: Poggiani
authors: Institute of Pharmacy, Pharmacology and Toxicology and Center of Molecular Biosciences Innsbruck, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria.
authors: Simone
authors: S
authors: Sartori
authors: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; INSERM, U661, F-34000 Montpellier, France; Universités de Montpellier 1 & 2, UMR-5203, F-34000 Montpellier, France; INSERM, U637, Montpellier, France.
authors: Matteo E
authors: ME
authors: Mangoni
authors: Institute of Pharmacy, Pharmacology and Toxicology and Center of Molecular Biosciences Innsbruck, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria.
authors: Martina J
authors: MJ
authors: Sinnegger-Brauns
authors: Department of Pharmacology and Center for Molecular Medicine, University of Cologne, Gleueler Strasse 24 and Robert-Koch-Strasse 21, D-50931 Cologne, Germany.
authors: Stefan
authors: S
authors: Herzig
authors: Institute of Pharmacy, Pharmacology and Toxicology and Center of Molecular Biosciences Innsbruck, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria. Electronic address: joerg.striessnig@uibk.ac.at.
authors: Jörg
authors: J
authors: Striessnig
authors: Institute of Pharmacy, Pharmacology and Toxicology and Center of Molecular Biosciences Innsbruck, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria. Electronic address: alexandra.koschak@meduniwien.ac.at.
authors: Alexandra
authors: A
authors: Koschak
mesh_terms: D017398:Alternative Splicing; D001703:Biophysics / Q000379:methods; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000737:chemistry; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D003001:Cloning, Molecular; D057809:HEK293 Cells; D006801:Humans; D007477:Ions; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D007477:Ions; D012313:RNA; D002118:Calcium