A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling

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A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling. / Gorvin, Caroline M; Babinsky, Valerie N; Malinauskas, Tomas; Nissen, Peter H; Schou, Anders J; Hanyaloglu, Aylin C; Siebold, Christian ; Jones, E Yvonne; Hannan, Fadil M; Thakker, Rajesh V.

In: Science signaling, Vol. 11, No. 518, eaan3714, 20.02.2018.

Research output: Contribution to journalArticlepeer-review

Harvard

Gorvin, CM, Babinsky, VN, Malinauskas, T, Nissen, PH, Schou, AJ, Hanyaloglu, AC, Siebold, C, Jones, EY, Hannan, FM & Thakker, RV 2018, 'A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling', Science signaling, vol. 11, no. 518, eaan3714. https://doi.org/10.1126/scisignal.aan3714

APA

Gorvin, C. M., Babinsky, V. N., Malinauskas, T., Nissen, P. H., Schou, A. J., Hanyaloglu, A. C., Siebold, C., Jones, E. Y., Hannan, F. M., & Thakker, R. V. (2018). A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling. Science signaling, 11(518), [eaan3714]. https://doi.org/10.1126/scisignal.aan3714

Vancouver

Author

Gorvin, Caroline M ; Babinsky, Valerie N ; Malinauskas, Tomas ; Nissen, Peter H ; Schou, Anders J ; Hanyaloglu, Aylin C ; Siebold, Christian ; Jones, E Yvonne ; Hannan, Fadil M ; Thakker, Rajesh V. / A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling. In: Science signaling. 2018 ; Vol. 11, No. 518.

Bibtex

@article{1cd5e689383641e2971bfd331f5b477b,
title = "A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling",
abstract = "The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through Gq/11 and Gi/o to stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-function CASR mutations, 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+i responses. 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 CaSRR680G in HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+i responses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11 and Gi/o and 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 Arg680 and 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-Glu767 salt bridge in mediating signaling bias.",
author = "Gorvin, {Caroline M} and Babinsky, {Valerie N} and Tomas Malinauskas and Nissen, {Peter H} and Schou, {Anders J} and Hanyaloglu, {Aylin C} and Christian Siebold and Jones, {E Yvonne} and Hannan, {Fadil M} and Thakker, {Rajesh V}",
year = "2018",
month = feb,
day = "20",
doi = "10.1126/scisignal.aan3714",
language = "English",
volume = "11",
journal = "Science signaling",
issn = "1945-0877",
publisher = "American Association for the Advancement of Science",
number = "518",

}

RIS

TY - JOUR

T1 - A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling

AU - Gorvin, Caroline M

AU - Babinsky, Valerie N

AU - Malinauskas, Tomas

AU - Nissen, Peter H

AU - Schou, Anders J

AU - Hanyaloglu, Aylin C

AU - Siebold, Christian

AU - Jones, E Yvonne

AU - Hannan, Fadil M

AU - Thakker, Rajesh V

PY - 2018/2/20

Y1 - 2018/2/20

N2 - The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through Gq/11 and Gi/o to stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-function CASR mutations, 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+i responses. 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 CaSRR680G in HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+i responses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11 and Gi/o and 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 Arg680 and 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-Glu767 salt bridge in mediating signaling bias.

AB - The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals through Gq/11 and Gi/o to stimulate cytosolic calcium (Ca2+i) and mitogen-activated protein kinase (MAPK) signaling to control extracellular calcium homeostasis. Studies of loss- and gain-of-function CASR mutations, 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+i responses. 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 CaSRR680G in HEK 293 cells showed that this mutation increased MAPK signaling without altering Ca2+i responses. Moreover, this gain of function in MAPK activity occurred independently of Gq/11 and Gi/o and 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 Arg680 and 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-Glu767 salt bridge in mediating signaling bias.

U2 - 10.1126/scisignal.aan3714

DO - 10.1126/scisignal.aan3714

M3 - Article

VL - 11

JO - Science signaling

JF - Science signaling

SN - 1945-0877

IS - 518

M1 - eaan3714

ER -