Thesis – Rachel BOURDON-ALONZEAU

Identification of protein interactions of the Cav3.2 calcium channel: characterization of the regulatory role of TMEM200a

Jury

• Céline Marionneau, CR, Institut du Thorax Nantes – Rapporteur
• Delphine Bichet, CR, IPMC Nice – Rapporteur
• Ana Reynders, CR, IBDM Marseille – Examiner
• Jean-Yves Le Guennec, Professeur, Université de Montpellier – Examiner
• Emmanuel Bourinet, DR, IGF, Université de Montpellier – Thesis supervisor

Résumé

T-type calcium channels are implicated in numerous neurological disorders, including epilepsy, ataxia, and pain. Although they are essential for neuronal excitability, second messenger pathways, and gene expression, their signaling partners remain poorly characterized. Here, we have established a comprehensive characterization of the Cav3.2 interactome using Cav3.2-GFP as bait in the hippocampus of Cav3.2^eGFP-floxed KI mice. Our data reveal that Cav3.2 integrates into several networks, including other ion channels, the cytoskeleton, the extracellular matrix, kinases, and ubiquitin ligases. We then focused on TMEM200a, an intracellular protein that modulates calcineurin and NFAT activity. In patch-clamp recordings in tsA cells, TMEM200a shifts the activation and inactivation of Cav3.2 to more depolarized potentials, thereby increasing the window current. TMEM200a also binds to calcineurin and inhibits its activity. We therefore identify TMEM200a as a new partner of Cav3.2 and highlight the central role of phosphorylation/dephosphorylation mechanisms in the regulation of T-type channels, as well as their integration into calcium pathways controlling transcription and synaptic dynamics.