Dataset Information

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

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

SUBMITTER: Gorvin CM

PROVIDER: S-EPMC5792449 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Gorvin Caroline M CM Rogers Angela A Hastoy Benoit B Tarasov Andrei I AI Frost Morten M Sposini Silvia S Inoue Asuka A Whyte Michael P MP Rorsman Patrik P Hanyaloglu Aylin C AC Breitwieser Gerda E GE Thakker Rajesh V RV

Cell reports 20180128 4

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-2σ subunit (AP2σ) on signaling by the class C GPCR calc ...[more]

PMID: 29420171

Similar Datasets

Project description:The extracellular calcium-sensing receptor (CaSR) controls vital bone cell functions such as cell growth, differentiation and apoptosis. The binding of the native agonist (Ca2+) to CaSR activates the receptor, which undergoes structural changes that trigger a cascade of events along the cellular signaling pathways. Strontium (in the form of soluble salts) has been found to also be a CaSR agonist. The activation of the receptor by Sr2+ is considered to be the major mechanism through which strontium exerts its anti-osteoporosis effect, mostly in postmenopausal women. Strontium-activated CaSR initiates a series of signal transduction events resulting in both osteoclast apoptosis and osteoblast differentiation, thus strengthening the bone tissue. The intimate mechanism of Sr2+ activation of CaSR is still enigmatic. Herewith, by employing a combination of density functional theory (DFT) calculations and polarizable continuum model (PCM) computations, we have found that the Ca2+ binding sites 1, 3, and 4 in the activated CaSR, although possessing a different number and type of protein ligands, overall structure and charge state, are all selective for Ca2+ over Sr2+. The three binding sites, regardless of their structural differences, exhibit almost equal metal selectivity if they are flexible and have no geometrical constraints on the incoming Sr2+. In contrast to Ca2+ and Sr2+, Mg2+ constructs, when allowed to fully relax during the optimization process, adopt their stringent six-coordinated octahedral structure at the expense of detaching a one-backbone carbonyl ligand and shifting it to the second coordination layer of the metal. The binding of Mg2+ and Sr2+ to a rigid/inflexible calcium-designed binding pocket requires an additional energy penalty for the binding ion; however, the price for doing so (to be paid by Sr2+) is much less than that of Mg2+. The results obtained delineate the key factors controlling the competition between metal cations for the receptor and shed light on some aspects of strontium's therapeutic effects.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets