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学科主题: 临床医学
题名:
Stereochemistry of an Agonist Determines Coupling Preference of beta(2)-Adrenoceptor to Different G Proteins in Cardiomyocytes
作者: 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
发表日期: 2009
DOI: 10.1124/mol.108.051078
卷: 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
项目资助者: National Institutes of Health ; National Institute on Aging
WOS记录号: WOS:000261854500017
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/49884
Appears in Collections:北京大学第二临床医学院_期刊论文

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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

Recommended Citation:
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.
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