It has recently been shown that prion protein (PrP) and the calcium channel auxiliary α2δ subunits interact in neurons and expression systems. We examined whether there was an effect of PrP on calcium currents. We show that when PrP is co-expressed with calcium channels formed from CaV2.1/β and α2δ-1 or α2δ-2, this results in a consistent decrease in calcium current density. This reduction was absent when PrP lacked its glycosyl-phosphatidylinositol (GPI) anchor. We have found that α2δ subunits are able to form GPI-anchored proteins [2] and present further evidence here. We have recently characterised a C-terminally truncated α2δ-1 construct, α2δ-1ΔC, and found that, despite loss of its membrane anchor, it still shows partial ability to increase calcium currents. 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 by cytosolic GFP, indicates that competition for limited GPI-anchor intermediates or trafficking proteins may be involved in PrP suppression of α2δ subunit function
