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 journalArticlepeer-review

31 Citations (Scopus)
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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 languageEnglish
Pages (from-to)1054-1066
Number of pages13
JournalCell Reports
Volume22
Issue number4
DOIs
Publication statusPublished - 23 Jan 2018

Keywords

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

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