Glycyrrhetic Acid Synergistically Enhances β2-Adrenergic Receptor-Gs Signaling by Changing the Location of Gαs in Lipid Rafts

Glycyrrhetic acid (GA) exerts synergistic anti-asthmatic effects via a β2-adrenergic receptor (β2AR)-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the β2AR-Gs-adenylate cyclase (AC)-mediated signaling pathway. Owing...

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Main Authors:	Shi, Qian, Hou, Yuanyuan, Hou, Jie, Pan, Penwei, Liu, Ze, Jiang, Min, Gao, Jie, Bai, Gang
Format:	Online
Language:	English
Published:	Public Library of Science 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459958/

id	pubmed-3459958
recordtype	oai_dc
spelling	pubmed-34599582012-10-01 Glycyrrhetic Acid Synergistically Enhances β2-Adrenergic Receptor-Gs Signaling by Changing the Location of Gαs in Lipid Rafts Shi, Qian Hou, Yuanyuan Hou, Jie Pan, Penwei Liu, Ze Jiang, Min Gao, Jie Bai, Gang Research Article Glycyrrhetic acid (GA) exerts synergistic anti-asthmatic effects via a β2-adrenergic receptor (β2AR)-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the β2AR-Gs-adenylate cyclase (AC)-mediated signaling pathway. Owing to the structural similarities between GA and cholesterol, we investigated the possibility that GA enhances β2AR signaling by altering cholesterol distribution. Azide-terminal GA (ATGA) was synthesized and applied to human embryonic kidney 293 (HEK293) cells expressing fusion β2AR, and the electron spin resonance (ESR) technique was utilized. GA was determined to be localized predominantly on membrane and decreased their cholesterol contents. Thus, the fluidity of the hydrophobic region increased but not the polar surface of the cell membrane. The conformations of membrane proteins were also changed. GA further changed the localization of Gαs from lipid rafts to non-raft regions, resulting the binding of β2AR and Gαs, as well as in reduced β2AR internalization. Co-localization of β2AR, Gαs, and AC increased isoproterenol-induced cAMP production and cholesterol reloading attenuated this effect. A speculation wherein GA enhances beta-adrenergic activity by increasing the functional linkage between the subcomponents of the membrane β2AR-protein kinase A (PKA) signaling pathway was proposed. The enhanced efficacy of β2AR agonists by this novel mechanism could prevent tachyphylaxis. Public Library of Science 2012-09-27 /pmc/articles/PMC3459958/ /pubmed/23028680 http://dx.doi.org/10.1371/journal.pone.0044921 Text en © 2012 Shi et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Shi, Qian Hou, Yuanyuan Hou, Jie Pan, Penwei Liu, Ze Jiang, Min Gao, Jie Bai, Gang
spellingShingle	Shi, Qian Hou, Yuanyuan Hou, Jie Pan, Penwei Liu, Ze Jiang, Min Gao, Jie Bai, Gang Glycyrrhetic Acid Synergistically Enhances β2-Adrenergic Receptor-Gs Signaling by Changing the Location of Gαs in Lipid Rafts
author_facet	Shi, Qian Hou, Yuanyuan Hou, Jie Pan, Penwei Liu, Ze Jiang, Min Gao, Jie Bai, Gang
author_sort	Shi, Qian
title	Glycyrrhetic Acid Synergistically Enhances β2-Adrenergic Receptor-Gs Signaling by Changing the Location of Gαs in Lipid Rafts
title_short	Glycyrrhetic Acid Synergistically Enhances β2-Adrenergic Receptor-Gs Signaling by Changing the Location of Gαs in Lipid Rafts
title_full	Glycyrrhetic Acid Synergistically Enhances β2-Adrenergic Receptor-Gs Signaling by Changing the Location of Gαs in Lipid Rafts
title_fullStr	Glycyrrhetic Acid Synergistically Enhances β2-Adrenergic Receptor-Gs Signaling by Changing the Location of Gαs in Lipid Rafts
title_full_unstemmed	Glycyrrhetic Acid Synergistically Enhances β2-Adrenergic Receptor-Gs Signaling by Changing the Location of Gαs in Lipid Rafts
title_sort	glycyrrhetic acid synergistically enhances β2-adrenergic receptor-gs signaling by changing the location of gαs in lipid rafts
description	Glycyrrhetic acid (GA) exerts synergistic anti-asthmatic effects via a β2-adrenergic receptor (β2AR)-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the β2AR-Gs-adenylate cyclase (AC)-mediated signaling pathway. Owing to the structural similarities between GA and cholesterol, we investigated the possibility that GA enhances β2AR signaling by altering cholesterol distribution. Azide-terminal GA (ATGA) was synthesized and applied to human embryonic kidney 293 (HEK293) cells expressing fusion β2AR, and the electron spin resonance (ESR) technique was utilized. GA was determined to be localized predominantly on membrane and decreased their cholesterol contents. Thus, the fluidity of the hydrophobic region increased but not the polar surface of the cell membrane. The conformations of membrane proteins were also changed. GA further changed the localization of Gαs from lipid rafts to non-raft regions, resulting the binding of β2AR and Gαs, as well as in reduced β2AR internalization. Co-localization of β2AR, Gαs, and AC increased isoproterenol-induced cAMP production and cholesterol reloading attenuated this effect. A speculation wherein GA enhances beta-adrenergic activity by increasing the functional linkage between the subcomponents of the membrane β2AR-protein kinase A (PKA) signaling pathway was proposed. The enhanced efficacy of β2AR agonists by this novel mechanism could prevent tachyphylaxis.
publisher	Public Library of Science
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459958/
_version_	1611912490477682688

Glycyrrhetic Acid Synergistically Enhances β2-Adrenergic Receptor-Gs Signaling by Changing the Location of Gαs in Lipid Rafts

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