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LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α(2)δ-1 subunit

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 traff...

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Autores principales: Kadurin, Ivan, Rothwell, Simon W., Lana, Beatrice, Nieto-Rostro, Manuela, Dolphin, Annette C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335561/
https://www.ncbi.nlm.nih.gov/pubmed/28256585
http://dx.doi.org/10.1038/srep43802
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author Kadurin, Ivan
Rothwell, Simon W.
Lana, Beatrice
Nieto-Rostro, Manuela
Dolphin, Annette C.
author_facet Kadurin, Ivan
Rothwell, Simon W.
Lana, Beatrice
Nieto-Rostro, Manuela
Dolphin, Annette C.
author_sort Kadurin, Ivan
collection PubMed
description 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.
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spelling pubmed-53355612017-03-07 LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α(2)δ-1 subunit Kadurin, Ivan Rothwell, Simon W. Lana, Beatrice Nieto-Rostro, Manuela Dolphin, Annette C. Sci Rep Article 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. Nature Publishing Group 2017-03-03 /pmc/articles/PMC5335561/ /pubmed/28256585 http://dx.doi.org/10.1038/srep43802 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Kadurin, Ivan
Rothwell, Simon W.
Lana, Beatrice
Nieto-Rostro, Manuela
Dolphin, Annette C.
LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α(2)δ-1 subunit
title LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α(2)δ-1 subunit
title_full LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α(2)δ-1 subunit
title_fullStr LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α(2)δ-1 subunit
title_full_unstemmed LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α(2)δ-1 subunit
title_short LRP1 influences trafficking of N-type calcium channels via interaction with the auxiliary α(2)δ-1 subunit
title_sort lrp1 influences trafficking of n-type calcium channels via interaction with the auxiliary α(2)δ-1 subunit
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335561/
https://www.ncbi.nlm.nih.gov/pubmed/28256585
http://dx.doi.org/10.1038/srep43802
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