Do voltage-gated calcium channel α₂δ subunits require proteolytic processing into α₂ and δ to be functional?

The accessory α₂δ subunits of voltage-gated calcium channels are type 1 transmembrane proteins that are highly glycosylated and possess multiple disulfide bonds. From studies of the topology and processing of skeletal-muscle α₂δ-1, it has been shown to be post-translationally cleaved into an α₂ and a δ subunit, which remain disulfide-bonded. In the present study, we have examined the processing of α₂δ-2 subunits when stably or transiently expressed, in tsA (temperature-sensitive A)-201, Cos-7 and NG108-15 cells, and compared it with that observed in the cerebellum. Despite showing full functionality and being expressed on the plasma membrane, the vast majority of heterologously expressed α₂δ-2 is not cleaved into α₂-2 and δ-2, unlike endogenous α₂δ-2 in the cerebellum. It remains an open question for future research whether α₂δ-2 is functional in its calcium channel trafficking role in its proteolytically cleaved or non-cleaved state.