Agonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-V1b receptor

Abstract During the development of analgesic tolerance to morphine, the V1b vasopressin receptor has been proposed to bind to β-arrestin 2 and the µ-opioid receptor to enable their interaction. However, direct evidence of such a high-order complex is lacking. Using bioluminescent resonance energy tr...

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Autores principales:	Nuttawadee Ngamlertwong, Hiroyoshi Tsuchiya, Yuta Mochimaru, Morio Azuma, Takahiro Kuchimaru, Taka-aki Koshimizu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6ce8f72b459e4c499d3b2445fcce5bfd
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spelling	oai:doaj.org-article:6ce8f72b459e4c499d3b2445fcce5bfd2021-12-02T14:53:42ZAgonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-V1b receptor10.1038/s41598-021-94894-y2045-2322https://doaj.org/article/6ce8f72b459e4c499d3b2445fcce5bfd2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94894-yhttps://doaj.org/toc/2045-2322Abstract During the development of analgesic tolerance to morphine, the V1b vasopressin receptor has been proposed to bind to β-arrestin 2 and the µ-opioid receptor to enable their interaction. However, direct evidence of such a high-order complex is lacking. Using bioluminescent resonance energy transfer between a split Nanoluciferase and the Venus fluorescent protein, the NanoBit-NanoBRET system, we found that β-arrestin 2 closely located near the heteromer µ-V1b receptor in the absence of an agonist and moved closer to the receptor carboxyl-termini upon agonist stimulation. An additive effect of the two agonists for opioid and vasopressin receptors was detected on the NanoBRET between the µ-V1b heteromer and β-arrestin 2. To increase the agonist response of NanoBRET, the ratio of the donor luminophore to the acceptor fluorophore was decreased to the detection limit of luminescence. In the first phase of access, β-arrestin 2 was likely to bind to the unstimulated V1b receptor in both its phosphorylated and unphosphorylated forms. In contrast, the second-phase access of β-arrestin 2 was agonist dependent, indicating a possible pharmacological intervention strategy. Therefore, our efficient method should be useful for evaluating chemicals that directly target the vasopressin binding site in the µ-V1b heteromer to reduce the second-phase access of β-arrestin 2 and thereby to alleviate tolerance to morphine analgesia.Nuttawadee NgamlertwongHiroyoshi TsuchiyaYuta MochimaruMorio AzumaTakahiro KuchimaruTaka-aki KoshimizuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nuttawadee Ngamlertwong Hiroyoshi Tsuchiya Yuta Mochimaru Morio Azuma Takahiro Kuchimaru Taka-aki Koshimizu Agonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-V1b receptor
description	Abstract During the development of analgesic tolerance to morphine, the V1b vasopressin receptor has been proposed to bind to β-arrestin 2 and the µ-opioid receptor to enable their interaction. However, direct evidence of such a high-order complex is lacking. Using bioluminescent resonance energy transfer between a split Nanoluciferase and the Venus fluorescent protein, the NanoBit-NanoBRET system, we found that β-arrestin 2 closely located near the heteromer µ-V1b receptor in the absence of an agonist and moved closer to the receptor carboxyl-termini upon agonist stimulation. An additive effect of the two agonists for opioid and vasopressin receptors was detected on the NanoBRET between the µ-V1b heteromer and β-arrestin 2. To increase the agonist response of NanoBRET, the ratio of the donor luminophore to the acceptor fluorophore was decreased to the detection limit of luminescence. In the first phase of access, β-arrestin 2 was likely to bind to the unstimulated V1b receptor in both its phosphorylated and unphosphorylated forms. In contrast, the second-phase access of β-arrestin 2 was agonist dependent, indicating a possible pharmacological intervention strategy. Therefore, our efficient method should be useful for evaluating chemicals that directly target the vasopressin binding site in the µ-V1b heteromer to reduce the second-phase access of β-arrestin 2 and thereby to alleviate tolerance to morphine analgesia.
format	article
author	Nuttawadee Ngamlertwong Hiroyoshi Tsuchiya Yuta Mochimaru Morio Azuma Takahiro Kuchimaru Taka-aki Koshimizu
author_facet	Nuttawadee Ngamlertwong Hiroyoshi Tsuchiya Yuta Mochimaru Morio Azuma Takahiro Kuchimaru Taka-aki Koshimizu
author_sort	Nuttawadee Ngamlertwong
title	Agonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-V1b receptor
title_short	Agonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-V1b receptor
title_full	Agonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-V1b receptor
title_fullStr	Agonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-V1b receptor
title_full_unstemmed	Agonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-V1b receptor
title_sort	agonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-v1b receptor
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6ce8f72b459e4c499d3b2445fcce5bfd
work_keys_str_mv	AT nuttawadeengamlertwong agonistdependencyofthesecondphaseaccessofbarrestin2totheheteromericμv1breceptor AT hiroyoshitsuchiya agonistdependencyofthesecondphaseaccessofbarrestin2totheheteromericμv1breceptor AT yutamochimaru agonistdependencyofthesecondphaseaccessofbarrestin2totheheteromericμv1breceptor AT morioazuma agonistdependencyofthesecondphaseaccessofbarrestin2totheheteromericμv1breceptor AT takahirokuchimaru agonistdependencyofthesecondphaseaccessofbarrestin2totheheteromericμv1breceptor AT takaakikoshimizu agonistdependencyofthesecondphaseaccessofbarrestin2totheheteromericμv1breceptor
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Agonist dependency of the second phase access of β-arrestin 2 to the heteromeric µ-V1b receptor

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