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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doaj-a620aa50861b4760af796663dffcd8952020-11-24T21:18:04ZengElsevierCell Reports2211-12472018-01-012241054106610.1016/j.celrep.2017.12.089AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein SelectivityCaroline M. Gorvin0Angela Rogers1Benoit Hastoy2Andrei I. Tarasov3Morten Frost4Silvia Sposini5Asuka Inoue6Michael P. Whyte7Patrik Rorsman8Aylin C. Hanyaloglu9Gerda E. Breitwieser10Rajesh V. Thakker11Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UKAcademic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UKDiabetes Research Laboratory, Radcliffe Department of Medicine, University of Oxford, Oxford, UKDiabetes Research Laboratory, Radcliffe Department of Medicine, University of Oxford, Oxford, UKAcademic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UKInstitute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, UKLaboratory of Molecular and Cellular Biochemistry, Tohoku University, Sendai, JapanCenter for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St. Louis, MO, USADiabetes Research Laboratory, Radcliffe Department of Medicine, University of Oxford, Oxford, UKInstitute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, UKGeisinger Clinic, Weis Center for Research, Department of Functional and Molecular Genomics, Danville, PA, USAAcademic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UKSpatial 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 Gαq/11 and Gαi/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 Gαq/11. Thus, compartmental bias for CaSR-mediated Gαq/11 endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling.http://www.sciencedirect.com/science/article/pii/S2211124717319265clathrin-mediated endocytosisadaptor protein-2GPCRcalcium signalinghypercalcemiaendosomal signalingG proteins |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Caroline M. Gorvin Angela Rogers Benoit Hastoy Andrei I. Tarasov Morten Frost Silvia Sposini Asuka Inoue Michael P. Whyte Patrik Rorsman Aylin C. Hanyaloglu Gerda E. Breitwieser Rajesh V. Thakker |
spellingShingle |
Caroline M. Gorvin Angela Rogers Benoit Hastoy Andrei I. Tarasov Morten Frost Silvia Sposini Asuka Inoue Michael P. Whyte Patrik Rorsman Aylin C. Hanyaloglu Gerda E. Breitwieser Rajesh V. Thakker AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity Cell Reports clathrin-mediated endocytosis adaptor protein-2 GPCR calcium signaling hypercalcemia endosomal signaling G proteins |
author_facet |
Caroline M. Gorvin Angela Rogers Benoit Hastoy Andrei I. Tarasov Morten Frost Silvia Sposini Asuka Inoue Michael P. Whyte Patrik Rorsman Aylin C. Hanyaloglu Gerda E. Breitwieser Rajesh V. Thakker |
author_sort |
Caroline M. Gorvin |
title |
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_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_sort |
ap2σ mutations impair calcium-sensing receptor trafficking and signaling, and show an endosomal pathway to spatially direct g-protein selectivity |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2018-01-01 |
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 Gαq/11 and Gαi/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 Gαq/11. Thus, compartmental bias for CaSR-mediated Gαq/11 endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling. |
topic |
clathrin-mediated endocytosis adaptor protein-2 GPCR calcium signaling hypercalcemia endosomal signaling G proteins |
url |
http://www.sciencedirect.com/science/article/pii/S2211124717319265 |
work_keys_str_mv |
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