Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors

G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors (7TMRs), typically interact with two distinct signal-transducers, i.e., G proteins and β-arrestins (βarrs). Interestingly, there are some non-canonical 7TMRs that lack G protein coupling but interact with barrs, althoug...

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Autores principales: Pandey, Shubhi, Kumari, Punita, Baidya, Mithu, Kise, Ryoji, Cao, Yubo, Dwivedi-Agnihotri, Hemlata, Banerjee, Ramanuj, Li, Xaria X., Cui, Cedric S., Lee, John D., Kawakami, Kouki, Maharana, Jagannath, Ranjan, Ashutosh, Chaturvedi, Madhu, Jhingan, Gagan Deep, Laporte, Stéphane A., Woodruff, Trent M., Inoue, Asuka, Shukla, Arun K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612807/
https://www.ncbi.nlm.nih.gov/pubmed/34582793
http://dx.doi.org/10.1016/j.molcel.2021.09.007
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author Pandey, Shubhi
Kumari, Punita
Baidya, Mithu
Kise, Ryoji
Cao, Yubo
Dwivedi-Agnihotri, Hemlata
Banerjee, Ramanuj
Li, Xaria X.
Cui, Cedric S.
Lee, John D.
Kawakami, Kouki
Maharana, Jagannath
Ranjan, Ashutosh
Chaturvedi, Madhu
Jhingan, Gagan Deep
Laporte, Stéphane A.
Woodruff, Trent M.
Inoue, Asuka
Shukla, Arun K.
author_facet Pandey, Shubhi
Kumari, Punita
Baidya, Mithu
Kise, Ryoji
Cao, Yubo
Dwivedi-Agnihotri, Hemlata
Banerjee, Ramanuj
Li, Xaria X.
Cui, Cedric S.
Lee, John D.
Kawakami, Kouki
Maharana, Jagannath
Ranjan, Ashutosh
Chaturvedi, Madhu
Jhingan, Gagan Deep
Laporte, Stéphane A.
Woodruff, Trent M.
Inoue, Asuka
Shukla, Arun K.
author_sort Pandey, Shubhi
collection PubMed
description G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors (7TMRs), typically interact with two distinct signal-transducers, i.e., G proteins and β-arrestins (βarrs). Interestingly, there are some non-canonical 7TMRs that lack G protein coupling but interact with barrs, although an understanding of their transducer coupling preference, downstream signaling, and structural mechanism remains elusive. Here, we characterize two such non-canonical 7TMRs, namely, the decoy D6 receptor (D6R) and the complement C5a receptor subtype 2 (C5aR2), in parallel with their canonical GPCR counterparts. We discover that D6R and C5aR2 efficiently couple to βarrs, exhibit distinct engagement of GPCR kinases (GRKs), and activate non-canonical downstream signaling pathways. We also observe that βarrs adopt distinct conformations for D6R and C5aR2, compared to their canonical GPCR counterparts, in response to common natural agonists. Our study establishes D6R and C5aR2 as βarr-coupled 7TMRs and provides key insights into their regulation and signaling with direct implication for biased agonism.
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spelling pubmed-76128072022-06-04 Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors Pandey, Shubhi Kumari, Punita Baidya, Mithu Kise, Ryoji Cao, Yubo Dwivedi-Agnihotri, Hemlata Banerjee, Ramanuj Li, Xaria X. Cui, Cedric S. Lee, John D. Kawakami, Kouki Maharana, Jagannath Ranjan, Ashutosh Chaturvedi, Madhu Jhingan, Gagan Deep Laporte, Stéphane A. Woodruff, Trent M. Inoue, Asuka Shukla, Arun K. Mol Cell Article G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors (7TMRs), typically interact with two distinct signal-transducers, i.e., G proteins and β-arrestins (βarrs). Interestingly, there are some non-canonical 7TMRs that lack G protein coupling but interact with barrs, although an understanding of their transducer coupling preference, downstream signaling, and structural mechanism remains elusive. Here, we characterize two such non-canonical 7TMRs, namely, the decoy D6 receptor (D6R) and the complement C5a receptor subtype 2 (C5aR2), in parallel with their canonical GPCR counterparts. We discover that D6R and C5aR2 efficiently couple to βarrs, exhibit distinct engagement of GPCR kinases (GRKs), and activate non-canonical downstream signaling pathways. We also observe that βarrs adopt distinct conformations for D6R and C5aR2, compared to their canonical GPCR counterparts, in response to common natural agonists. Our study establishes D6R and C5aR2 as βarr-coupled 7TMRs and provides key insights into their regulation and signaling with direct implication for biased agonism. 2021-11-18 2021-09-27 /pmc/articles/PMC7612807/ /pubmed/34582793 http://dx.doi.org/10.1016/j.molcel.2021.09.007 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pandey, Shubhi
Kumari, Punita
Baidya, Mithu
Kise, Ryoji
Cao, Yubo
Dwivedi-Agnihotri, Hemlata
Banerjee, Ramanuj
Li, Xaria X.
Cui, Cedric S.
Lee, John D.
Kawakami, Kouki
Maharana, Jagannath
Ranjan, Ashutosh
Chaturvedi, Madhu
Jhingan, Gagan Deep
Laporte, Stéphane A.
Woodruff, Trent M.
Inoue, Asuka
Shukla, Arun K.
Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors
title Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors
title_full Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors
title_fullStr Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors
title_full_unstemmed Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors
title_short Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors
title_sort intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612807/
https://www.ncbi.nlm.nih.gov/pubmed/34582793
http://dx.doi.org/10.1016/j.molcel.2021.09.007
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