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

Arnaud Monteil (1) , Patrick Chausson (2) , Katia Boutourlinsky (2) , Alexandre Mezghrani (1) , Iulia Blesneac (1) , Isabelle Bidaud (1) , Sylvaine Huc-Brandt (1) , Céline Lemmers (1) , Nathalie Leresche (2) , Régis C Lambert (2) , Philippe Lory (1)

1 IGF - Institut de Génomique Fonctionnelle
2 NPS - Neuroscience Paris Seine

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. Here we describe that co-expression of this I-II loop or its proximal region (⌬1-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, ⌬1-Cav3.2 inhibited both Cav3.2 and Cav3.1 but not Cav3.3 currents. Efficacy of ⌬1-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.

Domaines: Neurobiologie

Arnaud Monteil, Patrick Chausson, Katia Boutourlinsky, Alexandre Mezghrani, Iulia Blesneac, et al.. Inhibition of Cav3.2 T-type Calcium Channels by Its Intracellular I-II Loop. Journal of Biological Chemistry, 2015, 290 (26), pp.16168-16176. ⟨10.1074/jbc.M114.634261⟩. ⟨hal-01348945⟩