Imperial College London


Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Reader in Cell Biology



+44 (0)20 7594 2128a.hanyaloglu Website




Miss Kiran Dosanjh +44 (0)20 7594 2176




2009Institute of Reproductive and Developmental BiologyHammersmith Campus






BibTex format

author = {Gorvin, CM and Babinsky, VN and Malinauskas, T and Nissen, PH and Schou, AJ and Hanyaloglu, AC and Siebold, C and Jones, EY and Hannan, FM and Thakker, RV},
doi = {10.1126/scisignal.aan3714},
journal = {Science Signaling},
title = {A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling},
url = {},
volume = {11},
year = {2018}

RIS format (EndNote, RefMan)

AB - The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through Gq/11and Gi/oto stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-functionCASRmutations, which cause familial hypocalciuric hypercalcemia type 1 (FHH1) and autosomal dominant hypocalcemia type 1 (ADH1), respectively, have revealed that the CaSR signals in a biased manner. Thus, some mutations associated with FHH1 lead to signaling predominantly through the MAPK pathway, whereas mutations associated with ADH1 preferentially enhance Ca2+iresponses. We report a previously unidentified ADH1-associated R680G CaSR mutation, which led to the identification of a CaSR structural motif that mediates biased signaling. Expressing CaSRR680Gin HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+iresponses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11and Gi/oand was mediated instead by a noncanonical pathway involving β-arrestin proteins. Homology modeling and mutagenesis studies showed that the R680G CaSR mutation selectively enhanced β-arrestin signaling by disrupting a salt bridge formed between Arg680and Glu767, which are located in CaSR transmembrane domain 3 and extracellular loop 2, respectively. Thus, our results demonstrate CaSR signaling through β-arrestin and the importance of the Arg680-Glu767salt bridge in mediating signaling bias.
AU - Gorvin,CM
AU - Babinsky,VN
AU - Malinauskas,T
AU - Nissen,PH
AU - Schou,AJ
AU - Hanyaloglu,AC
AU - Siebold,C
AU - Jones,EY
AU - Hannan,FM
AU - Thakker,RV
DO - 10.1126/scisignal.aan3714
PY - 2018///
SN - 1937-9145
TI - A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling
T2 - Science Signaling
UR -
UR -
UR -
VL - 11
ER -