The inhibition of functional expression of calcium channels by prion protein demonstrates competition with α2δ for GPI-anchoring pathways

Anita Alvarez-Laviada, Ivan Kadurin, Assunta Senatore, Roberto Chiesa, Annette C. Dolphin

Research output: Contribution to journalArticlepeer-review

Abstract

It has been shown recently that PrP (prion protein) and the calcium channel auxiliary α2δ subunits interact in neurons and expression systems [Senatore, Colleoni, Verderio, Restelli, Morini, Condliffe, Bertani, Mantovani, Canovi, Micotti, Forloni, Dolphin, Matteoli, Gobbi and Chiesa (2012) Neuron 74, 300-313]. In the present study we examined whether therewas an effect of PrP on calcium currents. We have shown that when PrP is coexpressedwith calcium channels formed fromCaV2.1/β and α2δ-1 or α2δ-2, there is a consistent decrease in calcium current density. This reduction was absent when a PrP construct was used lacking its GPI (glycosylphosphatidylinositol) anchor. We have reported previously that α2δ subunits are able to form GPI-anchored proteins [Davies, Kadurin, Alvarez-Laviada, Douglas, Nieto-Rostro, Bauer, Pratt and Dolphin (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 1654-1659] and show further evidence in the present paper. We have characterized recently a C-terminally truncated α2δ-1 construct, α2δ-1C, and found that, despite loss of its membrane anchor, it still shows a partial ability to increase calcium currents [Kadurin, Alvarez-Laviada, Ng, Walker-Gray, D'Arco, Fadel, Pratt and Dolphin (2012) J. Biol. Chem. 1287, 33554-33566]. We now find that PrP does not inhibit CaV2.1/β currents formed with α2δ-1C, rather than α2δ-1. It is possible that PrP and α 2δ-1 compete for GPI-anchor intermediates or trafficking pathways, or that interaction between PrP and α2δ-1 requires association in cholesterol-rich membrane microdomains. Our additional finding that CaV2.1/β1b/α2δ-1 currents were inhibited by GPI-GFP, but not cytosolic GFP, indicates that competition for limited GPIanchor intermediates or trafficking pathways may be involved in PrP suppression of α2δ subunit function.

Original languageEnglish
Pages (from-to)365-374
Number of pages10
JournalBiochemical Journal
Volume458
Issue number2
DOIs
Publication statusPublished - Mar 1 2014

Keywords

  • αδ
  • Auxiliary subunit
  • Calcium channel
  • GPI anchor
  • Prion protein

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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