The inhibition of functional expression of calcium channels by prion protein demonstrates competition with α2δ for GPI-anchoring pathways
Author(s)
Alvarez-Laviada, A
Kadurin, I
Senatore, A
Chiesa, R
Dolphin, AC
Type
Journal Article
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 there was an effect of PrP on calcium currents. We have shown that when PrP is co-expressed with calcium channels formed from CaV2.1/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-1ΔC, 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-1ΔC, rather than α2δ-1. It is possible that PrP and α2δ-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 GPI-anchor intermediates or trafficking pathways may be involved in PrP suppression of α2δ subunit function.
Date Issued
2014-03-01
Date Acceptance
2014-03-01
Citation
Biochemical Journal, 2014, 458 (2), pp.365-374
ISSN
1470-8728
Publisher
Portland Press
Start Page
365
End Page
374
Journal / Book Title
Biochemical Journal
Volume
458
Issue
2
Copyright Statement
© 2014 The author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC-BY) (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Subjects
Animals
Binding, Competitive
Calcium Channels
Calcium Channels, N-Type
Female
Gene Expression Regulation
Glycosylphosphatidylinositols
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Prions
Protein Binding
Protein Transport
Rats
Signal Transduction
Xenopus
Biochemistry & Molecular Biology
06 Biological Sciences
11 Medical And Health Sciences
03 Chemical Sciences
Publication Status
Published