Dual function of the voltage-dependent Ca2+ channel α2δ subunit in current stimulation and subunit interaction

Abstract

Voltage-dependent Ca2+ channels are modulated by complex interactions with the α2δ subunit. In vitro translation was used to demonstrate a single transmembrane topology of the α2δ subunit in which all but the transmembrane sequence and 5 carboxy-terminal amino acids are extracellular. The glycosylated extracellular domain is required for current stimulation, as shown by coexpression of truncated α2δ subunits with α1A and β4 subunits in Xenopus oocytes and deglycosylation with peptide-N-glycosidase F. However, coexpression of the transmembrane domain-containing δ subunit reduced the stimulatory effects of full-length α2δ subunits and substitution of a different transmembrane domain resulted in a loss of current stimulation. These results support a model whereby the α2δ transmembrane domain mediates subunit interactions and the glycosylated extracellular domain enhances current amplitude.