AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity
Abstract
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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BibTeX
@article{gorvin2026ap2σ,
title = {{AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity}},
author = {Caroline Gorvin and Angela Rogers and Benoit Hastoy and Andrei Tarasov and Morten Frost and Silvia Sposini and Asuka Inoue and Michael Whyte and Patrik Rorsman and Aylin Hanyaloglu and Gerda Breitwieser and Rajesh Thakker},
journal = {Cell Reports},
year = {2026},
month = sep,
doi = {10.1016/j.celrep.2017.12.089},
url = {https://hal.science/hal-05767784v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity
AU - Caroline Gorvin
AU - Angela Rogers
AU - Benoit Hastoy
AU - Andrei Tarasov
AU - Morten Frost
AU - Silvia Sposini
AU - Asuka Inoue
AU - Michael Whyte
AU - Patrik Rorsman
AU - Aylin Hanyaloglu
AU - Gerda Breitwieser
AU - Rajesh Thakker
PY - 2026
DA - 2026/09/28
JO - Cell Reports
DO - 10.1016/j.celrep.2017.12.089
UR - https://hal.science/hal-05767784v1
AB - 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.
SN - 2211-1247
SN - 2211-1247
ER -