Ligand-directed bias of G protein signaling at the dopamine D2 receptor

Department of Drug Design and Pharmacology

Ligand-directed bias of G protein signaling at the dopamine D₂ receptor

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Ligand-directed bias of G protein signaling at the dopamine D₂ receptor. / Von Moo, Ee; Harpsøe, Kasper; Hauser, Alexander S; Masuho, Ikuo; Bräuner-Osborne, Hans; Gloriam, David E; Martemyanov, Kirill A.

In: Cell Chemical Biology, Vol. 29, No. 2, 2022, p. 226-238.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Von Moo, E, Harpsøe, K, Hauser, AS, Masuho, I, Bräuner-Osborne, H, Gloriam, DE & Martemyanov, KA 2022, 'Ligand-directed bias of G protein signaling at the dopamine D₂ receptor', Cell Chemical Biology, vol. 29, no. 2, pp. 226-238. https://doi.org/10.1016/j.chembiol.2021.07.004

APA

Von Moo, E., Harpsøe, K., Hauser, A. S., Masuho, I., Bräuner-Osborne, H., Gloriam, D. E., & Martemyanov, K. A. (2022). Ligand-directed bias of G protein signaling at the dopamine D₂ receptor. Cell Chemical Biology, 29(2), 226-238. https://doi.org/10.1016/j.chembiol.2021.07.004

Vancouver

Von Moo E, Harpsøe K, Hauser AS, Masuho I, Bräuner-Osborne H, Gloriam DE et al. Ligand-directed bias of G protein signaling at the dopamine D₂ receptor. Cell Chemical Biology. 2022;29(2):226-238. https://doi.org/10.1016/j.chembiol.2021.07.004

Author

Von Moo, Ee ; Harpsøe, Kasper ; Hauser, Alexander S ; Masuho, Ikuo ; Bräuner-Osborne, Hans ; Gloriam, David E ; Martemyanov, Kirill A. / Ligand-directed bias of G protein signaling at the dopamine D₂ receptor. In: Cell Chemical Biology. 2022 ; Vol. 29, No. 2. pp. 226-238.

Bibtex

@article{7dea0441ebd44206a01de6f77affae02,

title = "Ligand-directed bias of G protein signaling at the dopamine D2 receptor",

abstract = "G-protein-coupled receptors (GPCRs) represent the largest family of drug targets. Upon activation, GPCRs signal primarily via a diverse set of heterotrimeric G proteins. Most GPCRs can couple to several different G protein subtypes. However, how drugs act at GPCRs contributing to the selectivity of G protein recognition is poorly understood. Here, we examined the G protein selectivity profile of the dopamine D2 receptor (D2), a GPCR targeted by antipsychotic drugs. We show that D2 discriminates between six individual members of the Gi/o family, and its profile of functional selectivity is remarkably different across its ligands, which all engaged D2 with a distinct G protein coupling pattern. Using structural modeling, receptor mutagenesis, and pharmacological evaluation, we identified residues in the D2 binding pocket that shape these ligand-directed biases. We further provide pharmacogenomic evidence that natural variants in D2 differentially affect its G protein biases in response to different ligands.",

author = "{Von Moo}, Ee and Kasper Harps{\o}e and Hauser, {Alexander S} and Ikuo Masuho and Hans Br{\"a}uner-Osborne and Gloriam, {David E} and Martemyanov, {Kirill A}",

year = "2022",

doi = "10.1016/j.chembiol.2021.07.004",

language = "English",

volume = "29",

pages = "226--238",

journal = "Chemistry and Biology",

issn = "2451-9448",

publisher = "Elsevier",

number = "2",

}

RIS

TY - JOUR

T1 - Ligand-directed bias of G protein signaling at the dopamine D2 receptor

AU - Von Moo, Ee

AU - Harpsøe, Kasper

AU - Hauser, Alexander S

AU - Masuho, Ikuo

AU - Bräuner-Osborne, Hans

AU - Gloriam, David E

AU - Martemyanov, Kirill A

PY - 2022

Y1 - 2022

N2 - G-protein-coupled receptors (GPCRs) represent the largest family of drug targets. Upon activation, GPCRs signal primarily via a diverse set of heterotrimeric G proteins. Most GPCRs can couple to several different G protein subtypes. However, how drugs act at GPCRs contributing to the selectivity of G protein recognition is poorly understood. Here, we examined the G protein selectivity profile of the dopamine D2 receptor (D2), a GPCR targeted by antipsychotic drugs. We show that D2 discriminates between six individual members of the Gi/o family, and its profile of functional selectivity is remarkably different across its ligands, which all engaged D2 with a distinct G protein coupling pattern. Using structural modeling, receptor mutagenesis, and pharmacological evaluation, we identified residues in the D2 binding pocket that shape these ligand-directed biases. We further provide pharmacogenomic evidence that natural variants in D2 differentially affect its G protein biases in response to different ligands.

AB - G-protein-coupled receptors (GPCRs) represent the largest family of drug targets. Upon activation, GPCRs signal primarily via a diverse set of heterotrimeric G proteins. Most GPCRs can couple to several different G protein subtypes. However, how drugs act at GPCRs contributing to the selectivity of G protein recognition is poorly understood. Here, we examined the G protein selectivity profile of the dopamine D2 receptor (D2), a GPCR targeted by antipsychotic drugs. We show that D2 discriminates between six individual members of the Gi/o family, and its profile of functional selectivity is remarkably different across its ligands, which all engaged D2 with a distinct G protein coupling pattern. Using structural modeling, receptor mutagenesis, and pharmacological evaluation, we identified residues in the D2 binding pocket that shape these ligand-directed biases. We further provide pharmacogenomic evidence that natural variants in D2 differentially affect its G protein biases in response to different ligands.

U2 - 10.1016/j.chembiol.2021.07.004

DO - 10.1016/j.chembiol.2021.07.004

M3 - Journal article

C2 - 34302750

VL - 29

SP - 226

EP - 238

JO - Chemistry and Biology

JF - Chemistry and Biology

SN - 2451-9448

IS - 2

ER -

ID: 284402622