AP2σ mutations impair calcium-sensing receptor trafficking and signaling, and show an endosomal pathway to spatially direct G-Protein selectivity

Research output: Contribution to journalArticlepeer-review


  • 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

Colleges, School and Institutes


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.


Original languageEnglish
Pages (from-to)1054-1066
Number of pages13
JournalCell Reports
Issue number4
Publication statusPublished - 23 Jan 2018