University of Hertfordshire

From the same journal


  • 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
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Original languageEnglish
Pages (from-to)1054-1066
Number of pages13
JournalCell Reports
Publication statusPublished - 23 Jan 2018


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.


© 2017 The Author(s).

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