Lrp1 Influences Trafficking Of N-Type Calcium Channels Via Interaction With The Auxiliary Alpha(2)Delta-1 Subunit

Voltage-gated Ca2+ (Ca-V) channels consist of a pore-forming alpha 1 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 beta- and alpha(2)delta- subunits. The molecular mechanisms involved in alpha(2)delta subunit trafficking, and the effect of alpha(2)delta subunits on trafficking calcium channel complexes remain poorly understood. Here we show that alpha(2)delta-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 alpha(2)delta binding to gabapentin, and influences calcium channel trafficking and function. Whereas LRP1 alone reduces alpha(2)delta-1 trafficking to the cell-surface, the LRP1/RAP combination enhances mature glycosylation, proteolytic processing and cell-surface expression of alpha(2)delta-1, and also increase plasma-membrane expression and function of Ca(V)2.2 when co-expressed with alpha(2 delta)-1. Furthermore RAP alone produced a small increase in cell-surface expression of Ca(V)2.2, alpha(2 delta)-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 alpha(2)delta subunits.