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Voltage-gated Ca 2+  (Ca V ) channels consist of a pore-forming α1 subunit, which determines the main functional and pharmacological attributes of the channel. The Ca V 1 and Ca V 2 channels are associated with auxiliary β- and α 2 δ-subunits. The molecular mechanisms involved in α 2 δ subunit trafficking, and the effect of α 2 δ subunits on trafficking calcium channel complexes remain poorly understood. Here we show that α 2 δ-1 is a ligand for the Low Density Lipoprotein (LDL) Receptor-related Protein-1 (LRP1), a multifunctional receptor which mediates trafficking of cargoes. This interaction with LRP1 is direct, and is modulated by the LRP chaperone, Receptor-Associated Protein (RAP). LRP1 regulates α 2 δ binding to gabapentin, and influences calcium channel trafficking and function. Whereas LRP1 alone reduces α 2 δ-1 trafficking to the cell-surface, the LRP1/RAP combination enhances mature glycosylation, proteolytic processing and cell-surface expression of α 2 δ-1, and also increase plasma-membrane expression and function of Ca V 2.2 when co-expressed with α 2 δ-1. Furthermore RAP alone produced a small increase in cell-surface expression of Ca V 2.2, α 2 δ-1 and the associated calcium currents. It is likely to be interacting with an endogenous member of the LDL receptor family to have these effects. Our findings now provide a key insight and new tools to investigate the trafficking of calcium channel α 2 δ subunits.

LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α2δ-1 subunit