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

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

doi:10.1016/j.celrep.2017.12.089

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

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

Research output: Contribution to journal › Article › peer-review

69 Citations (Scopus)

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. Gorvin et al. show that the class C GPCR calcium-sensing receptor (CaSR) mediates signaling from plasma membranes using Gα_q/11 and Gα_i/o and from endosomes by using only Gα_q/11. Adaptor protein-2 σ subunit (AP2σ) mutations impair CaSR internalization, leading to reduced sustained endosomal signaling and hypercalcemia in humans.

Original language	English
Pages (from-to)	1054-1066
Number of pages	13
Journal	Cell Reports
Volume	22
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2017.12.089
Publication status	Published (in print/issue) - 23 Jan 2018

Funding

This work was supported by grants from the Medical Research Council ( G1000467 to C.M.G. and R.V.T.), National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (to R.V.T.), Shriners Hospitals for Children (to M.P.W.), and a Goodger and Schorstein Scholarship from the Radcliffe Department of Medicine, University of Oxford (to C.M.G.). R.V.T. has Senior Investigator Awards from the Wellcome Trust ( 106995/z/15/z ) and NIHR ( NF-SI-0514-10091 ). A.R. was a Wellcome Trust Clinical Training Fellow.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

adaptor protein-2
calcium signaling
clathrin-mediated endocytosis
endosomal signaling
G proteins
GPCR
hypercalcemia

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10.1016/j.celrep.2017.12.089

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Gorvin, C. M., Rogers, A., Hastoy, B., Tarasov, A. I., Frost, M., Sposini, S., Inoue, A., Whyte, M. P., Rorsman, P., Hanyaloglu, A. C., Breitwieser, G. E., & Thakker, R. V. (2018). AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity. Cell Reports, 22(4), 1054-1066. https://doi.org/10.1016/j.celrep.2017.12.089

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title = "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 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. Gorvin et al. show that the class C GPCR calcium-sensing receptor (CaSR) mediates signaling from plasma membranes using Gαq/11 and Gαi/o and from endosomes by using only Gαq/11. Adaptor protein-2 σ subunit (AP2σ) mutations impair CaSR internalization, leading to reduced sustained endosomal signaling and hypercalcemia in humans.",

keywords = "adaptor protein-2, calcium signaling, clathrin-mediated endocytosis, endosomal signaling, G proteins, GPCR, hypercalcemia",

author = "Gorvin, \{Caroline M.\} and Angela Rogers and Benoit Hastoy and Tarasov, \{Andrei I.\} and Morten Frost and Silvia Sposini and Asuka Inoue and Whyte, \{Michael P.\} and Patrik Rorsman and Hanyaloglu, \{Aylin C.\} and Breitwieser, \{Gerda E.\} and Thakker, \{Rajesh V.\}",

year = "2018",

month = jan,

day = "23",

doi = "10.1016/j.celrep.2017.12.089",

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Gorvin, CM, Rogers, A, Hastoy, B, Tarasov, AI, Frost, M, Sposini, S, Inoue, A, Whyte, MP, Rorsman, P, Hanyaloglu, AC, Breitwieser, GE & Thakker, RV 2018, 'AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity', Cell Reports, vol. 22, no. 4, pp. 1054-1066. https://doi.org/10.1016/j.celrep.2017.12.089

TY - JOUR

T1 - AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity

AU - Gorvin, Caroline M.

AU - Rogers, Angela

AU - Hastoy, Benoit

AU - Tarasov, Andrei I.

AU - Frost, Morten

AU - Sposini, Silvia

AU - Inoue, Asuka

AU - Whyte, Michael P.

AU - Rorsman, Patrik

AU - Hanyaloglu, Aylin C.

AU - Breitwieser, Gerda E.

AU - Thakker, Rajesh V.

PY - 2018/1/23

Y1 - 2018/1/23

N2 - 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. Gorvin et al. show that the class C GPCR calcium-sensing receptor (CaSR) mediates signaling from plasma membranes using Gαq/11 and Gαi/o and from endosomes by using only Gαq/11. Adaptor protein-2 σ subunit (AP2σ) mutations impair CaSR internalization, leading to reduced sustained endosomal signaling and hypercalcemia in humans.

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 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. Gorvin et al. show that the class C GPCR calcium-sensing receptor (CaSR) mediates signaling from plasma membranes using Gαq/11 and Gαi/o and from endosomes by using only Gαq/11. Adaptor protein-2 σ subunit (AP2σ) mutations impair CaSR internalization, leading to reduced sustained endosomal signaling and hypercalcemia in humans.

KW - adaptor protein-2

KW - calcium signaling

KW - clathrin-mediated endocytosis

KW - endosomal signaling

KW - G proteins

KW - GPCR

KW - hypercalcemia

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DO - 10.1016/j.celrep.2017.12.089

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AN - SCOPUS:85044843504

SN - 2211-1247

VL - 22

SP - 1054

EP - 1066

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

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

Abstract

Funding

UN SDGs

Keywords

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