AP2 sigma Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity

作者：Gorvin Caroline M; Rogers Angela; Hastoy Benoit; Tarasov Andrei I; Frost Morten; Sposini Silvia; Inoue Asuka; Whyte Michael P; Rorsman Patrik; Hanyaloglu Aylin C; Breitwieser Gerda E; Thakker Rajesh V^*

来源：Cell Reports, 2018, 22(4): 1054-1066.

DOI：10.1016/j.celrep.2017.12.089

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 sigma subunit (AP2 sigma) on signaling by the class C GPCR calcium-sensing receptor (CaSR). These AP2 sigma mutations increase CaSR PM expression yet paradoxically reduce CaSR signaling. Hypercalcemia-associated AP2 sigma mutations reduced CaSR signaling via G alpha(q/11) and G alpha(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 G alpha(q/11). Thus, compartmental bias for CaSR-mediated G alpha(q/11) endomembrane signaling provides a mechanistic basis for multidimensional GPCR signaling.

• 出版日期2018-1-23