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      Modulation of Voltage- and Ca 2+-dependent Gating of Ca V1.3 L-type Calcium Channels by Alternative Splicing of a C-terminal Regulatory Domain*

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          Abstract

          Low voltage activation of Ca V1.3 L-type Ca 2+ channels controls excitability in sensory cells and central neurons as well as sinoatrial node pacemaking. Ca V1.3-mediated pacemaking determines neuronal vulnerability of dopaminergic striatal neurons affected in Parkinson disease. We have previously found that in Ca V1.4 L-type Ca 2+ channels, activation, voltage, and calcium-dependent inactivation are controlled by an intrinsic distal C-terminal modulator. Because alternative splicing in the Ca V1.3 α1 subunit C terminus gives rise to a long (Ca V1.3 42) and a short form (Ca V1.3 42A), we investigated if a C-terminal modulatory mechanism also controls Ca V1.3 gating. The biophysical properties of both splice variants were compared after heterologous expression together with β3 and α2δ1 subunits in HEK-293 cells. Activation of calcium current through Ca V1.3 42A channels was more pronounced at negative voltages, and inactivation was faster because of enhanced calcium-dependent inactivation. By investigating several Ca V1.3 channel truncations, we restricted the modulator activity to the last 116 amino acids of the C terminus. The resulting Ca V1.3 ΔC116 channels showed gating properties similar to Ca V1.3 42A that were reverted by co-expression of the corresponding C-terminal peptide C 116. Fluorescence resonance energy transfer experiments confirmed an intramolecular protein interaction in the C terminus of Ca V1.3 channels that also modulates calmodulin binding. These experiments revealed a novel mechanism of channel modulation enabling cells to tightly control Ca V1.3 channel activity by alternative splicing. The absence of the C-terminal modulator in short splice forms facilitates Ca V1.3 channel activation at lower voltages expected to favor Ca V1.3 activity at threshold voltages as required for modulation of neuronal firing behavior and sinoatrial node pacemaking.

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          Rapid planetesimal formation in turbulent circumstellar discs

          The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.
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            The Dicke Quantum Phase Transition with a Superfluid Gas in an Optical Cavity

            A phase transition describes the sudden change of state in a physical system, such as the transition between a fluid and a solid. Quantum gases provide the opportunity to establish a direct link between experiment and generic models which capture the underlying physics. A fundamental concept to describe the collective matter-light interaction is the Dicke model which has been predicted to show an intriguing quantum phase transition. Here we realize the Dicke quantum phase transition in an open system formed by a Bose-Einstein condensate coupled to an optical cavity, and observe the emergence of a self-organized supersolid phase. The phase transition is driven by infinitely long-ranged interactions between the condensed atoms. These are induced by two-photon processes involving the cavity mode and a pump field. We show that the phase transition is described by the Dicke Hamiltonian, including counter-rotating coupling terms, and that the supersolid phase is associated with a spontaneously broken spatial symmetry. The boundary of the phase transition is mapped out in quantitative agreement with the Dicke model. The work opens the field of quantum gases with long-ranged interactions, and provides access to novel quantum phases.
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              Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels.

              Voltage-gated L-type Ca2+ channels (LTCCs) containing a pore-forming alpha1D subunit (D-LTCCs) are expressed in neurons and neuroendocrine cells. Their relative contribution to total L-type Ca2+ currents and their physiological role and significance as a drug target remain unknown. Therefore, we generated D-LTCC deficient mice (alpha1D-/-) that were viable with no major disturbances of glucose metabolism. alpha1D-/-mice were deaf due to the complete absence of L-type currents in cochlear inner hair cells and degeneration of outer and inner hair cells. In wild-type controls, D-LTCC-mediated currents showed low activation thresholds and slow inactivation kinetics. Electrocardiogram recordings revealed sinoatrial node dysfunction (bradycardia and arrhythmia) in alpha1D-/- mice. We conclude that alpha1D can form LTCCs with negative activation thresholds essential for normal auditory function and control of cardiac pacemaker activity.
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                Author and article information

                Journal
                J Biol Chem
                jbc
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology
                0021-9258
                1083-351X
                25 July 2008
                25 July 2008
                : 283
                : 30
                : 20733-20744
                Affiliations
                []Institute of Pharmacy, Pharmacology, and Toxicology, and Center for Molecular Biosciences, University of Innsbruck, Peter-Mayr-Strasse 1/I, A-6020 Innsbruck, Austria, [§ ]Institute of Biophysics, University of Linz, Altenbergerstrasse 69, A-4040 Linz, Austria, and []Institute of Physiology II and Tübingen Hearing Research Centre, University of Tübingen, D-72076 Tübingen, Germany
                Author notes
                [1 ] To whom correspondence should be addressed. Tel.: 43-512-507-5602; Fax: 42-512-507-2931; E-mail: alexandra.koschak@ 123456uibk.ac.at .
                Article
                20733
                10.1074/jbc.M802254200
                2475692
                18482979
                066749a4-eb56-4a9d-b2bf-3a99d8caa19f
                Copyright © 2008, The American Society for Biochemistry and Molecular Biology, Inc.

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                History
                : 21 March 2008
                : 13 May 2008
                Categories
                Mechanisms of Signal Transduction

                Biochemistry
                Biochemistry

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