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J. Biol. Chem., Vol. 283, Issue 30, 20733-20744, July 25, 2008

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Modulation of Voltage- and Ca²⁺-dependent Gating of Ca_V1.3 L-type Calcium Channels by Alternative Splicing of a C-terminal Regulatory Domain^*

Anamika Singh, Mathias Gebhart, Reinhard Fritsch, Martina J. Sinnegger-Brauns, Chiara Poggiani, Jean-Charles Hoda, Jutta Engel^¶, Christoph Romanin, Jörg Striessnig, and Alexandra Koschak¹

From the 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

Low voltage activation of Ca_V1.3 L-type Ca²⁺ 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 Ca²⁺ channels, activation, voltage, and calcium-dependent inactivation are controlled by an intrinsic distal C-terminal modulator. Because alternative splicing in the Ca_V1.3 1 subunit C terminus gives rise to a long (Ca_V1.3₄₂) 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 21 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_C116 channels showed gating properties similar to Ca_V1.3_42A that were reverted by co-expression of the corresponding C-terminal peptide C₁₁₆. 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.

Received for publication, March 21, 2008 , and in revised form, May 13, 2008.

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^* This work was supported by the Austrian Science Funds P17159 [GenBank] (to J. S.) and P18169 [GenBank] (to C. R.), the Tyrolean Science Fund UNI-0404/353 (to A. K.), European Community Grant Cavnet, MRTN-CT-2006-35367, and the University of Innsbruck. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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¹ To whom correspondence should be addressed. Tel.: 43-512-507-5602; Fax: 42-512-507-2931; E-mail: alexandra.koschak{at}uibk.ac.at.

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