β1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes

Abstract β1-adrenergic receptors (β1ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth-regulatory pathways. Structural studies of the β1AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intr...

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Autores principales:	Misun Park, Gopireddy R. Reddy, Gerd Wallukat, Yang K. Xiang, Susan F. Steinberg
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dcbfc13e7f234e8282b710543fd712ef
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spelling	oai:doaj.org-article:dcbfc13e7f234e8282b710543fd712ef2021-12-02T15:04:52Zβ1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes10.1038/s41598-017-06607-z2045-2322https://doaj.org/article/dcbfc13e7f234e8282b710543fd712ef2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06607-zhttps://doaj.org/toc/2045-2322Abstract β1-adrenergic receptors (β1ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth-regulatory pathways. Structural studies of the β1AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intracellular surface of the β1AR, but the extracellular N-terminus, which is a target for post-translational modifications, typically is ignored. This study identifies β1AR N-terminal O-glycosylation at Ser37/Ser41 as a mechanism that prevents β1AR N-terminal cleavage. We used an adenoviral overexpression strategy to show that both full-length/glycosylated β1ARs and N-terminally truncated glycosylation-defective β1ARs couple to cAMP and ERK-MAPK signaling pathways in cardiomyocytes. However, a glycosylation defect that results in N-terminal truncation stabilizes β1ARs in a conformation that is biased toward the cAMP pathway. The identification of O-glycosylation and N-terminal cleavage as novel structural determinants of β1AR responsiveness in cardiomyocytes could be exploited for therapeutic advantage.Misun ParkGopireddy R. ReddyGerd WallukatYang K. XiangSusan F. SteinbergNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Misun Park Gopireddy R. Reddy Gerd Wallukat Yang K. Xiang Susan F. Steinberg β1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes
description	Abstract β1-adrenergic receptors (β1ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth-regulatory pathways. Structural studies of the β1AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intracellular surface of the β1AR, but the extracellular N-terminus, which is a target for post-translational modifications, typically is ignored. This study identifies β1AR N-terminal O-glycosylation at Ser37/Ser41 as a mechanism that prevents β1AR N-terminal cleavage. We used an adenoviral overexpression strategy to show that both full-length/glycosylated β1ARs and N-terminally truncated glycosylation-defective β1ARs couple to cAMP and ERK-MAPK signaling pathways in cardiomyocytes. However, a glycosylation defect that results in N-terminal truncation stabilizes β1ARs in a conformation that is biased toward the cAMP pathway. The identification of O-glycosylation and N-terminal cleavage as novel structural determinants of β1AR responsiveness in cardiomyocytes could be exploited for therapeutic advantage.
format	article
author	Misun Park Gopireddy R. Reddy Gerd Wallukat Yang K. Xiang Susan F. Steinberg
author_facet	Misun Park Gopireddy R. Reddy Gerd Wallukat Yang K. Xiang Susan F. Steinberg
author_sort	Misun Park
title	β1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes
title_short	β1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes
title_full	β1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes
title_fullStr	β1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes
title_full_unstemmed	β1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes
title_sort	β1-adrenergic receptor o-glycosylation regulates n-terminal cleavage and signaling responses in cardiomyocytes
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/dcbfc13e7f234e8282b710543fd712ef
work_keys_str_mv	AT misunpark b1adrenergicreceptoroglycosylationregulatesnterminalcleavageandsignalingresponsesincardiomyocytes AT gopireddyrreddy b1adrenergicreceptoroglycosylationregulatesnterminalcleavageandsignalingresponsesincardiomyocytes AT gerdwallukat b1adrenergicreceptoroglycosylationregulatesnterminalcleavageandsignalingresponsesincardiomyocytes AT yangkxiang b1adrenergicreceptoroglycosylationregulatesnterminalcleavageandsignalingresponsesincardiomyocytes AT susanfsteinberg b1adrenergicreceptoroglycosylationregulatesnterminalcleavageandsignalingresponsesincardiomyocytes
_version_	1718389048573165568

β1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes

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