FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4387361208> ?p ?o ?g. }

• W4387361208 abstract "Abstract Disclosure: R. Wyatt: None. C.M. Gorvin: None. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a fundamental role in extracellular calcium homeostasis by activating Gαq/11 and Gαi/o signaling to regulate parathyroid hormone (PTH) release. CaSR can also continue signaling once internalised (known as sustained signaling) to elicit responses that are distinct from those at the plasma membrane. Loss-of-function mutations of CaSR cause familial hypocalciuric hypercalcemia type 1 (FHH1), while Arg15 mutations in the adaptor protein-2 σ-subunit (AP2σ) cause FHH3, by impairing CaSR internalisation and disrupting sustained signaling. However, the sustained signaling pathway has been incompletely defined and the effects of allosteric modulators on the process are unknown. Here we examined CaSR membrane trafficking and G protein activation in different endomembrane compartments using bystander BRET and HILO advanced imaging in HEK293 cells. This showed that internalised CaSR is targeted to Rab5-positive early endosomes and Rab4-positive early-to-recycling membranes, and not to degradation pathways as previously hypothesised. CaSR exclusively recruits active Gq/11 to early endosome membranes to drive sustained signals that produce distinct transcriptional profiles than those from plasma membranes. We next mutated a C-terminal region within CaSR predicted to form a dileucine endocytic motif that interacts with AP2σ. NanoBiT assays confirmed that the CaSR-dileucine mutant disrupted interactions between CaSR and AP2σ to the same magnitude as AP2σ-Arg15 mutations. Moreover, this CaSR-dileucine mutant impaired CaSR internalisation and reduced Gq/11 sustained signals from Rab5 and Rab4 endosomes to similar levels to those observed in cells expressing the FHH3-associated AP2σ-Arg15 mutant. Gi/o and G12/13 responses from plasma membranes were not affected by the CaSR-dileucine mutant. Finally, we assessed whether the CaSR positive allosteric modulator, cinacalcet, affects sustained signalling. When exposed to cinacalcet CaSR significantly increased the recruitment of active Gq/11 to early endosomes, resulting in a significant increase in signaling, while signals from the plasma membrane were not different to vehicle-treated cells. In summary, we have demonstrated that CaSR is targeted to an early-to-recycling endosomal pathway, which could explain how CaSR responds rapidly to fluctutations in serum calcium to maintain calcium homeostasis. Moreover, we have defined the endocytic motif within the CaSR required for sustained signaling and shown that cinacalcet is a spatially-biased allosteric modulator of the CaSR that preferentially enhances signaling from endosomal membranes. Thus, FHH3-associated AP2σ mutations, CaSR dileucine mutants and cinacalcet can be used as tools to better understand CaSR spatiotemporal signaling and define its physiological significance. Presentation: Thursday, June 15, 2023" @default.
• W4387361208 created "2023-10-06" @default.
• W4387361208 creator A5003616755 @default.
• W4387361208 creator A5011297390 @default.
• W4387361208 date "2023-10-01" @default.
• W4387361208 modified "2023-10-06" @default.
• W4387361208 title "OR03-05 Cinacalcet Acts As A Spatially Biased Allosteric Modulator To Enhance CaSR Signaling From Endosomal Membranes" @default.
• W4387361208 doi "https://doi.org/10.1210/jendso/bvad114.436" @default.
• W4387361208 hasPublicationYear "2023" @default.
• W4387361208 type Work @default.
• W4387361208 citedByCount "0" @default.
• W4387361208 crossrefType "journal-article" @default.
• W4387361208 hasAuthorship W4387361208A5003616755 @default.
• W4387361208 hasAuthorship W4387361208A5011297390 @default.
• W4387361208 hasBestOaLocation W43873612081 @default.
• W4387361208 hasConcept C102747710 @default.
• W4387361208 hasConcept C135285700 @default.
• W4387361208 hasConcept C142590548 @default.
• W4387361208 hasConcept C166342909 @default.
• W4387361208 hasConcept C170493617 @default.
• W4387361208 hasConcept C178790620 @default.
• W4387361208 hasConcept C185592680 @default.
• W4387361208 hasConcept C2781208988 @default.
• W4387361208 hasConcept C28005876 @default.
• W4387361208 hasConcept C519063684 @default.
• W4387361208 hasConcept C55493867 @default.
• W4387361208 hasConcept C62478195 @default.
• W4387361208 hasConcept C79747257 @default.
• W4387361208 hasConcept C79879829 @default.
• W4387361208 hasConcept C86803240 @default.
• W4387361208 hasConcept C95444343 @default.
• W4387361208 hasConceptScore W4387361208C102747710 @default.
• W4387361208 hasConceptScore W4387361208C135285700 @default.
• W4387361208 hasConceptScore W4387361208C142590548 @default.
• W4387361208 hasConceptScore W4387361208C166342909 @default.
• W4387361208 hasConceptScore W4387361208C170493617 @default.
• W4387361208 hasConceptScore W4387361208C178790620 @default.
• W4387361208 hasConceptScore W4387361208C185592680 @default.
• W4387361208 hasConceptScore W4387361208C2781208988 @default.
• W4387361208 hasConceptScore W4387361208C28005876 @default.
• W4387361208 hasConceptScore W4387361208C519063684 @default.
• W4387361208 hasConceptScore W4387361208C55493867 @default.
• W4387361208 hasConceptScore W4387361208C62478195 @default.
• W4387361208 hasConceptScore W4387361208C79747257 @default.
• W4387361208 hasConceptScore W4387361208C79879829 @default.
• W4387361208 hasConceptScore W4387361208C86803240 @default.
• W4387361208 hasConceptScore W4387361208C95444343 @default.
• W4387361208 hasIssue "Supplement_1" @default.
• W4387361208 hasLocation W43873612081 @default.
• W4387361208 hasOpenAccess W4387361208 @default.
• W4387361208 hasPrimaryLocation W43873612081 @default.
• W4387361208 hasRelatedWork W131364339 @default.
• W4387361208 hasRelatedWork W1492038278 @default.
• W4387361208 hasRelatedWork W2072311845 @default.
• W4387361208 hasRelatedWork W2140820666 @default.
• W4387361208 hasRelatedWork W2148338791 @default.
• W4387361208 hasRelatedWork W2165456024 @default.
• W4387361208 hasRelatedWork W2400526229 @default.
• W4387361208 hasRelatedWork W2830758472 @default.
• W4387361208 hasRelatedWork W3048027417 @default.
• W4387361208 hasRelatedWork W2187104674 @default.
• W4387361208 hasVolume "7" @default.
• W4387361208 isParatext "false" @default.
• W4387361208 isRetracted "false" @default.
• W4387361208 workType "article" @default.