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Ubiquitin-specific protease USP2-45 acts as a molecular switch to promote α2δ-1-induced downregulation of Cav1.2 channels

Rougier, Jean-Sebastien ; Albesa, Maxime ; Syam, Ninda ; Halet, Guillaume ; Abriel, Hugues ; Viard, Patricia

In: Pflügers Archiv - European Journal of Physiology, 2015, vol. 467, no. 9, p. 1919-1929

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    Titre
    • Ubiquitin-specific protease USP2-45 acts as a molecular switch to promote α2δ-1-induced downregulation of Cav1.2 channels
    Auteur
    • Rougier, Jean-Sebastien. Department of Neurosciences, Physiology, and Pharmacology, University College London, WC1E 6BT, London, UK
    • Albesa, Maxime. Department of Clinical Research, University of Bern, 3010, Bern, Switzerland
    • Syam, Ninda. Department of Clinical Research, University of Bern, 3010, Bern, Switzerland
    • Halet, Guillaume. CNRS, UMR 6290, Institut de Génétique et Développement de Rennes, 35043, Rennes, France
    • Abriel, Hugues. Department of Clinical Research, University of Bern, 3010, Bern, Switzerland
    • Viard, Patricia. Department of Neurosciences, Physiology, and Pharmacology, University College London, WC1E 6BT, London, UK
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • Pflügers Archiv - European Journal of Physiology, 2015, vol. 467, no. 9, p. 1919-1929. Springer Berlin Heidelberg
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:332299
    Summary
    Availability of voltage-gated calcium channels (Cav) at the plasma membrane is paramount to maintaining the calcium homeostasis of the cell. It is proposed that the ubiquitylation/de-ubiquitylation balance regulates the density of ion channels at the cell surface. Voltage-gated calcium channels Cav1.2 have been found to be ubiquitylated under basal conditions both in vitro and in vivo. In a previous study, we have shown that Cav1.2 channels are ubiquitylated by neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4-1) ubiquitin ligases, but the identity of the counterpart de-ubiquitylating enzyme remained to be elucidated. Regarding sodium and potassium channels, it has been reported that the action of the related isoform Nedd4-2 is counteracted by the ubiquitin-specific protease (USP) 2-45. In this study, we show that USP 2-45 also de-ubiquitylates Cav channels. We co-expressed USPs and Cav1.2 channels together with the accessory subunits β2 and α2δ-1, in tsA-201 and HEK-293 mammalian cell lines. Using whole-cell current recordings and surface biotinylation assays, we show that USP2-45 specifically decreases both the amplitude of Cav currents and the amount of Cav1.2 subunits inserted at the plasma membrane. Importantly, co-expression of the α2δ-1 accessory subunit is necessary to support the effect of USP2-45. We further show that USP2-45 promotes the de-ubiquitylation of both Cav1.2 and α2δ-1 subunits. Remarkably, α2δ-1, but not Cav1.2 nor β2, co-precipitated with USP2-45. These results suggest that USP2-45 binding to α2δ-1 promotes the de-ubiquitylation of both Cav1.2 and α2δ-1 subunits, in order to regulate the expression of Cav1.2 channels at the plasma membrane.