Inhibition of Cav3.2 T-type Calcium Channels by Its

J. Biol. Chem. · Jun 2015

Inhibition of Cav3.2 T-type Calcium Channels by Its Intracellular I-II Loop.

Voltage-dependent calcium channels (Cav) of the T-type family (Cav3.1, Cav3.2, and Cav3.3) are activated by low threshold membrane depolarization and contribute greatly to neuronal network excitability. Enhanced T-type channel activity, especially Cav3.2, contributes to disease states, including absence epilepsy. Interestingly, the intracellular loop connecting domains I and II (I-II loop) of Cav3.2 channels is implicated in the control of both surface expression and channel gating, indicating that this I-II loop plays an important regulatory role in T-type current. ⋯ Efficacy of Δ1-Cav3.2 to inhibit native T-type channels was assessed in thalamic neurons using viral transduction. We describe that T-type current was significantly inhibited in the ventrobasal neurons that express Cav3.1, whereas in nucleus reticularis thalami neurons that express Cav3.2 and Cav3.3 channels, only the fast inactivating T-type current (Cav3.2 component) was significantly inhibited. Altogether, these data describe a new strategy to differentially inhibit Cav3 isoforms of the T-type calcium channels.

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- Arnaud Monteil, Patrick Chausson, Katia Boutourlinsky, Alexandre Mezghrani, Sylvaine Huc-Brandt, Iulia Blesneac, Isabelle Bidaud, Céline Lemmers, Nathalie Leresche, Régis C Lambert, and Philippe Lory.
- From the Université de Montpellier, CNRS UMR 5203, Département de Physiologie, Institut de Génomique Fonctionnelle, Montpellier, F-34094 France, INSERM, U1191, Montpellier, F-34094 France, Plateforme de Vectorologie, Biocampus Montpellier CNRS UMS 3426, INSERM US009, Montpellier, F-34094 France, LabEx "Ion Channel Science and Therapeutics," Montpellier, F-34094 France.
- J. Biol. Chem. 2015 Jun 26; 290 (26): 16168-76.
AbstractVoltage-dependent calcium channels (Cav) of the T-type family (Cav3.1, Cav3.2, and Cav3.3) are activated by low threshold membrane depolarization and contribute greatly to neuronal network excitability. Enhanced T-type channel activity, especially Cav3.2, contributes to disease states, including absence epilepsy. Interestingly, the intracellular loop connecting domains I and II (I-II loop) of Cav3.2 channels is implicated in the control of both surface expression and channel gating, indicating that this I-II loop plays an important regulatory role in T-type current. Here we describe that co-expression of this I-II loop or its proximal region (Δ1-Cav3.2; Ser(423)-Pro(542)) together with recombinant full-length Cav3.2 channel inhibited T-type current without affecting channel expression and membrane incorporation. Similar T-type current inhibition was obtained in NG 108-15 neuroblastoma cells that constitutively express Cav3.2 channels. Of interest, Δ1-Cav3.2 inhibited both Cav3.2 and Cav3.1 but not Cav3.3 currents. Efficacy of Δ1-Cav3.2 to inhibit native T-type channels was assessed in thalamic neurons using viral transduction. We describe that T-type current was significantly inhibited in the ventrobasal neurons that express Cav3.1, whereas in nucleus reticularis thalami neurons that express Cav3.2 and Cav3.3 channels, only the fast inactivating T-type current (Cav3.2 component) was significantly inhibited. Altogether, these data describe a new strategy to differentially inhibit Cav3 isoforms of the T-type calcium channels.© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

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Inhibition of Cav3.2 T-type Calcium Channels by Its Intracellular I-II Loop.

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