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

• Main Authors: 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
• Format: Article
• Language: English
• Published: Elsevier 2018-01-01
• Series: Cell Reports
• Subjects: clathrin-mediated endocytosis; adaptor protein-2; GPCR; calcium signaling; hypercalcemia; endosomal signaling; G proteins
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124717319265

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.