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学科主题临床医学
Stereochemistry of an Agonist Determines Coupling Preference of beta(2)-Adrenoceptor to Different G Proteins in Cardiomyocytes
Woo, Anthony Yiu-Ho1; Wang, Tian-Bing3; Zeng, Xiaokun1; Zhu, Weizhong1; Abernethy, Darrell R.2; Wainer, Irving W.2; Xiao, Rui-Ping1
刊名MOLECULAR PHARMACOLOGY
2009
DOI10.1124/mol.108.051078
75期:1页:158-165
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Pharmacology & Pharmacy
研究领域[WOS]Pharmacology & Pharmacy
关键词[WOS]DILATED ISCHEMIC CARDIOMYOPATHY ; BETA(2) ADRENERGIC-RECEPTOR ; FAILING HUMAN-HEART ; CARDIAC MYOCYTES ; FUNCTIONAL SELECTIVITY ; CONFORMATIONAL-CHANGES ; SUBTYPE ; FAILURE ; KINASE ; STIMULATION
英文摘要

A fundamental question regarding receptor-G protein interaction is whether different agonists can lead a receptor to different intracellular signaling pathways. Our previous studies have demonstrated that although most beta(2)-adrenoceptor agonists activate both G(s) and G(i) proteins, fenoterol, a full agonist of beta(2)adrenoceptor, selectively activates G(s) protein. Fenoterol contains two chiral centers and may exist as four stereoisomers. We have synthesized a series of stereoisomers of fenoterol and its derivatives and characterized their receptor binding and pharmacological properties. We tested the hypothesis that the stereochemistry of an agonist determines selectivity of receptor coupling to different G protein(s). We found that the R, R isomers of fenoterol and methoxyfenoterol exhibited more potent effects to increase cardiomyocyte contraction than their S, R isomers. It is noteworthy that although (R,R)-fenoterol and (R,R)-methoxyfenoterol preferentially activate G(s) signaling, their S, R isomers were able to activate both G(s) and G(i) proteins as evidenced by the robust pertussis toxin sensitivities of their effects on cardiomyocyte contraction and on phosphorylation of extracellular signal-regulated kinase 1/2. The differential G protein selectivities of the fenoterol stereoisomers were further confirmed by photoaffinity labeling studies on G(s), G(i2), and G(i3) proteins. The inefficient G(i) signaling with the R, R isomers is not caused by the inability of the R, R isomers to trigger the protein kinase A (PKA)-mediated phosphorylation of the beta(2)-adrenoceptor, because the R, R isomers also markedly increased phosphorylation of the receptor at serine 262 by PKA. We conclude that in addition to receptor subtype and phosphorylation status, the stereochemistry of a given agonist plays an important role in determining receptor-G protein selectivity and downstream signaling events.

语种英语
WOS记录号WOS:000261854500017
资助机构National Institutes of Health ; National Institute on Aging
引用统计
被引频次:64[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/49884
专题北京大学第二临床医学院
作者单位1.NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA
2.NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA
3.Peking Univ, Peoples Hosp, Dept Orthopaed & Trauma, Beijing 100871, Peoples R China
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GB/T 7714
Woo, Anthony Yiu-Ho,Wang, Tian-Bing,Zeng, Xiaokun,et al. Stereochemistry of an Agonist Determines Coupling Preference of beta(2)-Adrenoceptor to Different G Proteins in Cardiomyocytes[J]. MOLECULAR PHARMACOLOGY,2009,75(1):158-165.
APA Woo, Anthony Yiu-Ho.,Wang, Tian-Bing.,Zeng, Xiaokun.,Zhu, Weizhong.,Abernethy, Darrell R..,...&Xiao, Rui-Ping.(2009).Stereochemistry of an Agonist Determines Coupling Preference of beta(2)-Adrenoceptor to Different G Proteins in Cardiomyocytes.MOLECULAR PHARMACOLOGY,75(1),158-165.
MLA Woo, Anthony Yiu-Ho,et al."Stereochemistry of an Agonist Determines Coupling Preference of beta(2)-Adrenoceptor to Different G Proteins in Cardiomyocytes".MOLECULAR PHARMACOLOGY 75.1(2009):158-165.
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