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AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity

Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic...

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Autores principales: Gorvin, Caroline M., Rogers, Angela, Hastoy, Benoit, Tarasov, Andrei I., Frost, Morten, Sposini, Silvia, Inoue, Asuka, Whyte, Michael P., Rorsman, Patrik, Hanyaloglu, Aylin C., Breitwieser, Gerda E., Thakker, Rajesh V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792449/
https://www.ncbi.nlm.nih.gov/pubmed/29420171
http://dx.doi.org/10.1016/j.celrep.2017.12.089
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author Gorvin, Caroline M.
Rogers, Angela
Hastoy, Benoit
Tarasov, Andrei I.
Frost, Morten
Sposini, Silvia
Inoue, Asuka
Whyte, Michael P.
Rorsman, Patrik
Hanyaloglu, Aylin C.
Breitwieser, Gerda E.
Thakker, Rajesh V.
author_facet Gorvin, Caroline M.
Rogers, Angela
Hastoy, Benoit
Tarasov, Andrei I.
Frost, Morten
Sposini, Silvia
Inoue, Asuka
Whyte, Michael P.
Rorsman, Patrik
Hanyaloglu, Aylin C.
Breitwieser, Gerda E.
Thakker, Rajesh V.
author_sort Gorvin, Caroline M.
collection PubMed
description Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic signaling via multiple G-protein pathways remain unknown. Here, we investigated the effects of disease-causing mutations of the adaptor protein-2 σ subunit (AP2σ) on signaling by the class C GPCR calcium-sensing receptor (CaSR). These AP2σ mutations increase CaSR PM expression yet paradoxically reduce CaSR signaling. Hypercalcemia-associated AP2σ mutations reduced CaSR signaling via Gα(q/11) and Gα(i/o) pathways. The mutations also delayed CaSR internalization due to prolonged residency time of CaSR in clathrin structures that impaired or abolished endosomal signaling, which was predominantly mediated by Gα(q/11). Thus, compartmental bias for CaSR-mediated Gα(q/11) endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling.
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spelling pubmed-57924492018-02-08 AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity Gorvin, Caroline M. Rogers, Angela Hastoy, Benoit Tarasov, Andrei I. Frost, Morten Sposini, Silvia Inoue, Asuka Whyte, Michael P. Rorsman, Patrik Hanyaloglu, Aylin C. Breitwieser, Gerda E. Thakker, Rajesh V. Cell Rep Article Spatial control of G-protein-coupled receptor (GPCR) signaling, which is used by cells to translate complex information into distinct downstream responses, is achieved by using plasma membrane (PM) and endocytic-derived signaling pathways. The roles of the endomembrane in regulating such pleiotropic signaling via multiple G-protein pathways remain unknown. Here, we investigated the effects of disease-causing mutations of the adaptor protein-2 σ subunit (AP2σ) on signaling by the class C GPCR calcium-sensing receptor (CaSR). These AP2σ mutations increase CaSR PM expression yet paradoxically reduce CaSR signaling. Hypercalcemia-associated AP2σ mutations reduced CaSR signaling via Gα(q/11) and Gα(i/o) pathways. The mutations also delayed CaSR internalization due to prolonged residency time of CaSR in clathrin structures that impaired or abolished endosomal signaling, which was predominantly mediated by Gα(q/11). Thus, compartmental bias for CaSR-mediated Gα(q/11) endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling. Cell Press 2018-01-28 /pmc/articles/PMC5792449/ /pubmed/29420171 http://dx.doi.org/10.1016/j.celrep.2017.12.089 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gorvin, Caroline M.
Rogers, Angela
Hastoy, Benoit
Tarasov, Andrei I.
Frost, Morten
Sposini, Silvia
Inoue, Asuka
Whyte, Michael P.
Rorsman, Patrik
Hanyaloglu, Aylin C.
Breitwieser, Gerda E.
Thakker, Rajesh V.
AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity
title AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity
title_full AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity
title_fullStr AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity
title_full_unstemmed AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity
title_short AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity
title_sort ap2σ mutations impair calcium-sensing receptor trafficking and signaling, and show an endosomal pathway to spatially direct g-protein selectivity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792449/
https://www.ncbi.nlm.nih.gov/pubmed/29420171
http://dx.doi.org/10.1016/j.celrep.2017.12.089
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