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Agonist-directed sorting of β2-adrenergic receptor signaling and its therapeutic implication in heart

郑州大学学报(医学版) 2000年第1期35卷 37-45页

作者： ZHANG Shengjun,XIAO Ruiping,ZHOU Yingying,Meike Kuschel,XIA Xianmin,Richard A.Bond ,Olga V.Fedorova,Alex Y.Bagrov,C.Wiuiam Balke,Edward G.Lakatta,CHEN Heping Laboratory of Cardiovascular Science ,Gerontology Research Center,NIA,NIH,Baltimore,MD 21224

Cardiac β 2 adrenergic receptor (AR) dually couples to G s and to pertussis toxin(PTX) sensitive G i proteins ,resulting in opposing effects on cell *** we show that the coupling preference of β 2AR to the bifurcated signaling pathways,tested over wide ranges of agonist concentrations and receptor densities,is determined by agonist *** β 2AR agonists including zinterol,procaterol or salbutamol activate concurrent G s and G i signaling in both rat and mouse ventricular myocytes,as evidenced by a marked potentiating effect of PTX on contractile ***,however ,sorts the β 2AR primarily to G s signaling,as evidenced by the lack of effect of *** results were observed in transgenic mice overexpressing human β *** cells from failing rat hearts where the contractile response to zinterol was severely depressed due to an up regulation of G i,fenoterol,which activates G s bypassing the G i signaling pathway,rescued the diminished β 2AR ***,agonist directed sorting of receptor stimulus affords a novel therapeutic strategy to enhance desired “signaling specific”effects while avoiding adverse side effects of therapeutic agents.

关键词： adrenergic beta receptor agonists G protein toxins cell contra-ctihty

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Signaling-selective β2-adrenergic stimulation:therapeutic implications in chronic heart failure

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郑州大学学报(医学版) 2000年第1期35卷 28-36页

作者： ZHANG Shengjun 1) ,ZHOU Yingying 1) ,ZHU Weizhong 1) ,WANG Dingji 1) ,Andrej Chruscinski 2) ,Brian K.Kobilka 2) ,Edward G.Lakatta 1) ,CHENG Heping 1) ,XIAO Ruiping 1) 1)Laboratory of Cardiovascular Science,Gerontology Research Center,National Institute on Aging,National Institutes of Health,Baltimore,MD 21224 2)Howard Hughes Medical Institute,Stanford University Medical Center,Stanford,CA 94305

The cardiac β 2 adrenergic receptor(AR)couples dually to G s and G i proteins,resulting in opposing effects on *** human chronic heart failure(HF),impaired β AR response is associated with increased G i signaling and selective downregulation of β 1 AR (higher β 2/β 1).Here we demonstrate that inhibition of G i with pertussis toxin restores the β 2 AR mediated contractile response in myocytes from two rat HF *** importantly,fenoterol,which selectively activates β 2 AR/G s,bypassing β 2 AR/G i signaling,revives fully the β 2 AR inotropic effect in the absence of pertussis *** conclude that an enhanced G i signaling underlies the HF associated dysfunction of β 2 AR,and that selective activation of β 2 AR/G s signaling by fenoterol may provide a novel therapeutic strategy for treatment of HF.

关键词： adrenergic beta receptor agonists G-proteins chronic heart failure animal

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