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 journalArticle

21 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 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.

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

Keywords

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

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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