The inhibition of functional expression of calcium channels by prion protein demonstrates competition with {alpha}2{delta} for GPI-anchoring pathways

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.
Source: BJ Signal - Category: Biochemistry Authors: Tags: BJ Signal Source Type: research