title: LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α2δ-1 subunit.
abstract: Voltage-gated Ca2+(CaV) channels consist of a pore-forming α1 subunit, which determines the main functional and pharmacological attributes of the channel. The CaV1 and CaV2 channels are associated with auxiliary β- and α2δ-subunits. The molecular mechanisms involved in α2δ subunit trafficking, and the effect of α2δ subunits on trafficking calcium channel complexes remain poorly understood. Here we show that α2δ-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 α2δ binding to gabapentin, and influences calcium channel trafficking and function. Whereas LRP1 alone reduces α2δ-1 trafficking to the cell-surface, the LRP1/RAP combination enhances mature glycosylation, proteolytic processing and cell-surface expression of α2δ-1, and also increase plasma-membrane expression and function of CaV2.2 when co-expressed with α2δ-1. Furthermore RAP alone produced a small increase in cell-surface expression of CaV2.2, α2δ-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 α2δ subunits.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Kadurin
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Rothwell
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Lana
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Manuela
authors.initials: M
authors.lastname: Nieto-Rostro
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
authors.forename: Annette C
authors.initials: AC
authors.lastname: Dolphin
mesh_terms: D000588:Amines / Q000378:metabolism; D000818:Animals; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism; D000077206:Gabapentin; D006801:Humans; D026563:LDL-Receptor Related Protein-Associated Protein / Q000235:genetics / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D011869:Radioligand Assay; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000588:Amines; D020864:Calcium Channels, N-Type; D003509:Cyclohexanecarboxylic Acids; D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D021122:Protein Subunits; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin