Calcium currents are enhanced by α2δ-1 lacking its membrane anchor.

The accessory α(2)δ subunits of voltage-gated calcium channels are membrane-anchored proteins, which are highly glycosylated, possess multiple disulfide bonds, and are post-translationally cleaved into α(2) and δ. All α(2)δ subunits have a C-terminal hydrophobic, potentially trans-membrane domain and were described as type I transmembrane proteins, but we found evidence that they can be glycosylphosphatidylinositol-anchored. To probe further the function of membrane anchoring in α(2)δ subunits, we have now examined the properties of α(2)δ-1 constructs truncated at their putative glycosylphosphatidylinositol anchor site, located before the C-terminal hydrophobic domain (α(2)δ-1ΔC-term). We find that the majority of α(2)δ-1ΔC-term is soluble and secreted into the medium, but unexpectedly, some of the protein remains associated with detergent-resistant membranes, also termed lipid rafts, and is extrinsically bound to the plasma membrane. Furthermore, heterologous co-expression of α(2)δ-1ΔC-term with Ca(V)2.1/β1b results in a substantial enhancement of the calcium channel currents, albeit less than that produced by wild-type α(2)δ-1. These results call into question the role of membrane anchoring of α(2)δ subunits for calcium current enhancement.