Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss

Abstract Regulators of G protein signaling (RGS) accelerate the GTPase activity of G proteins to enable rapid termination of the signals triggered by G protein-coupled receptors (GPCRs). Activation of several GPCRs, including cannabinoid receptor 2 (CB2R) and adenosine A1 receptor (A1AR), protects a...

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Autores principales:	Asmita Dhukhwa, Raheem F. H. Al Aameri, Sandeep Sheth, Debashree Mukherjea, Leonard Rybak, Vickram Ramkumar
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f7bd4bab02fb490bac2efed2eca9e9b6
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spelling	oai:doaj.org-article:f7bd4bab02fb490bac2efed2eca9e9b62021-12-02T15:51:15ZRegulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss10.1038/s41598-021-87387-52045-2322https://doaj.org/article/f7bd4bab02fb490bac2efed2eca9e9b62021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87387-5https://doaj.org/toc/2045-2322Abstract Regulators of G protein signaling (RGS) accelerate the GTPase activity of G proteins to enable rapid termination of the signals triggered by G protein-coupled receptors (GPCRs). Activation of several GPCRs, including cannabinoid receptor 2 (CB2R) and adenosine A1 receptor (A1AR), protects against noise and drug-induced ototoxicity. One such drug, cisplatin, an anticancer agent used to treat various solid tumors, produces permanent hearing loss in experimental animals and in a high percentage of cancer patients who undergo treatments. In this study we show that cisplatin induces the expression of the RGS17 gene and increases the levels of RGS17 protein which contributes to a significant proportion of the hearing loss. Knockdown of RGS17 suppressed cisplatin-induced hearing loss in male Wistar rats, while overexpression of RGS17 alone produced hearing loss in vivo. Furthermore, RGS17 and CB2R negatively regulate the expression of each other. These data suggest that RGS17 mediates cisplatin ototoxicity by uncoupling cytoprotective GPCRs from their normal G protein interactions, thereby mitigating the otoprotective contributions of endogenous ligands of these receptors. Thus, RGS17 represents a novel mediator of cisplatin ototoxicity and a potential therapeutic target for treating hearing loss.Asmita DhukhwaRaheem F. H. Al AameriSandeep ShethDebashree MukherjeaLeonard RybakVickram RamkumarNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Asmita Dhukhwa Raheem F. H. Al Aameri Sandeep Sheth Debashree Mukherjea Leonard Rybak Vickram Ramkumar Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss
description	Abstract Regulators of G protein signaling (RGS) accelerate the GTPase activity of G proteins to enable rapid termination of the signals triggered by G protein-coupled receptors (GPCRs). Activation of several GPCRs, including cannabinoid receptor 2 (CB2R) and adenosine A1 receptor (A1AR), protects against noise and drug-induced ototoxicity. One such drug, cisplatin, an anticancer agent used to treat various solid tumors, produces permanent hearing loss in experimental animals and in a high percentage of cancer patients who undergo treatments. In this study we show that cisplatin induces the expression of the RGS17 gene and increases the levels of RGS17 protein which contributes to a significant proportion of the hearing loss. Knockdown of RGS17 suppressed cisplatin-induced hearing loss in male Wistar rats, while overexpression of RGS17 alone produced hearing loss in vivo. Furthermore, RGS17 and CB2R negatively regulate the expression of each other. These data suggest that RGS17 mediates cisplatin ototoxicity by uncoupling cytoprotective GPCRs from their normal G protein interactions, thereby mitigating the otoprotective contributions of endogenous ligands of these receptors. Thus, RGS17 represents a novel mediator of cisplatin ototoxicity and a potential therapeutic target for treating hearing loss.
format	article
author	Asmita Dhukhwa Raheem F. H. Al Aameri Sandeep Sheth Debashree Mukherjea Leonard Rybak Vickram Ramkumar
author_facet	Asmita Dhukhwa Raheem F. H. Al Aameri Sandeep Sheth Debashree Mukherjea Leonard Rybak Vickram Ramkumar
author_sort	Asmita Dhukhwa
title	Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss
title_short	Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss
title_full	Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss
title_fullStr	Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss
title_full_unstemmed	Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss
title_sort	regulator of g protein signaling 17 represents a novel target for treating cisplatin induced hearing loss
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f7bd4bab02fb490bac2efed2eca9e9b6
work_keys_str_mv	AT asmitadhukhwa regulatorofgproteinsignaling17representsanoveltargetfortreatingcisplatininducedhearingloss AT raheemfhalaameri regulatorofgproteinsignaling17representsanoveltargetfortreatingcisplatininducedhearingloss AT sandeepsheth regulatorofgproteinsignaling17representsanoveltargetfortreatingcisplatininducedhearingloss AT debashreemukherjea regulatorofgproteinsignaling17representsanoveltargetfortreatingcisplatininducedhearingloss AT leonardrybak regulatorofgproteinsignaling17representsanoveltargetfortreatingcisplatininducedhearingloss AT vickramramkumar regulatorofgproteinsignaling17representsanoveltargetfortreatingcisplatininducedhearingloss
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Regulator of G protein signaling 17 represents a novel target for treating cisplatin induced hearing loss

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