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TRENDS PHARMACOL SCI:G蛋白偶联受体激活模式的新见解

2018-03-03 MedSci MedSci原创

G蛋白偶联受体(GPCR)是最大的细胞表面受体家族,参与几乎所有生命活动。其功能异常是导致包括心血管疾病、肿瘤、代谢性疾病和神经变性疾病等重大疾病的主要机制。因此,GPCR是最重要的药物靶点,约40%的临床用药靶点都是GPCR。相关研究已经获得了10次诺贝尔奖,其重要程度可见一斑。

G蛋白偶联受体(GPCR)是最大的细胞表面受体家族,参与几乎所有生命活动。其功能异常是导致包括心血管疾病、肿瘤、代谢性疾病和神经变性疾病等重大疾病的主要机制。因此,GPCR是最重要的药物靶点,约40%的临床用药靶点都是GPCR。相关研究已经获得了10次诺贝尔奖,其重要程度可见一斑。

GPCR作为膜受体,其激活是启动生理功能和病理作用的使动环节,也是药物精准研发的关键靶点。因此,GPCR激活机制的研究成为前沿热点。一些新的激活现象不断被发现,突破人们对受体激活经典认识。但面临的问题是,大量GPCR激活相关研究文章所揭示的机制缺乏理论上的提升和系统总结。

北京大学第三医院李子健课题组长期从事GPCR激活机制与心血管疾病的研究。日前,Cell Press旗下的综述期刊Trends in Pharmacological Sciences 在线发表了李子健课题组题为“New Insights into Modes of GPCR Activation”的综述文章,对于全面理解GPCR生理病理过程中复杂的启动模式以及开发靶向GPCR精准药物的全新策略具有重要指导意义和理论价值。

文章结合该团队在GPCR激活机制研究经验和积累,以经典“GPCR-G”激活模式为基础,总结提炼了5种主要新型激活模式(细胞内激活、偏向激活、聚化激活、转位激活和双相激活,下图),阐释了5种新型激活模式的本质区别和内在的联系,展望了新激活模式对疾病和药物研发理念的引领作用,提出了在生理、病理情况下多种激活模式如何独立工作和相互整合的独立观点。文章对于全面理解GPCR生理病理过程中复杂的启动模式以及开发靶向GPCR精准药物的全新策略具有重要指导意义和理论价值。

GPCR激活的经典模式和新模式. (A) Classical mode, (B) biased activation, (C) intracellular activation, (D) dimerization activation, (E) transactivation, and (F) biphasic activation.

北京大学第三医院博士生王文景和硕士生乔钰惠为本综述的并列第一作者,北京大学第三医院李子健研究员为通讯作者。李子健研究员专注于GPCR受体与心血管疾病的研究,作为通讯作者在The FASEB Journal、J Biol Chem.、British Journal of Pharmacology、Molecular Pharmacology等杂志系列发表SCI论文70余篇。2013年起任国际药理学著名杂志“Molecular Pharmacology” 编委,于2017年推动Molecular Pharmacology杂志出版中国专刊,并作为特邀主编组稿了国内该领域著名专家的最新成果,专刊发表在Molecular Pharmacology杂志,同时受该杂志主编邀请撰写了关于受体及受体调控的特邀评述文章,推进了我国药理学家在国际的影响力。


原始出处:
Wenjing Wang, Yuhui Qiao,  Zijian Li,et al.New Insights into Modes of GPCR Activation,Trends in Pharmacological Sciences,2018.DOI: https://doi.org/10.1016/j.tips.2018.01.001

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    2018-04-29 freve
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    2018-09-22 jj000001
  4. 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encryptionId=ed881120ec8, topicName=MAC)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4b65161, createdName=yb6560, createdTime=Sun Jul 22 20:31:00 CST 2018, time=2018-07-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1788293, encodeId=42281e88293ce, content=<a href='/topic/show?id=38e014162e2' target=_blank style='color:#2F92EE;'>#Pharmacol#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=59, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14162, encryptionId=38e014162e2, topicName=Pharmacol)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=930e243, createdName=dingxiaobo, createdTime=Tue May 29 08:31:00 CST 2018, time=2018-05-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1811541, encodeId=756218115413f, content=<a href='/topic/show?id=552688630bf' target=_blank style='color:#2F92EE;'>#蛋白偶联#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=95, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=88630, encryptionId=552688630bf, topicName=蛋白偶联)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=5c0050, createdName=lishiwen, createdTime=Mon Jan 14 03:31:00 CST 2019, time=2019-01-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1715527, encodeId=ea9e1e1552760, content=<a href='/topic/show?id=b1f58362e8' target=_blank style='color:#2F92EE;'>#G蛋白#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=80, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=8362, encryptionId=b1f58362e8, topicName=G蛋白)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=91a331951491, createdName=12498f1em18(暂无昵称), createdTime=Tue Mar 06 00:31:00 CST 2018, time=2018-03-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1785284, encodeId=6e791e852846a, content=<a href='/topic/show?id=51906e79a6' target=_blank style='color:#2F92EE;'>#ENDS#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=6779, encryptionId=51906e79a6, topicName=ENDS)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=82ba2500166, createdName=ms1467340776200723, createdTime=Tue Apr 03 11:31:00 CST 2018, time=2018-04-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1746944, encodeId=75d01e4694414, content=<a href='/topic/show?id=165b836349' target=_blank style='color:#2F92EE;'>#G蛋白偶联受体#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=115, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=8363, encryptionId=165b836349, topicName=G蛋白偶联受体)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=601235881674, createdName=huiwelcome, createdTime=Sat Mar 10 17:31:00 CST 2018, time=2018-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=292609, encodeId=50a129260958, content=优质资源.共同学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib06iaV3D9Tg5K0LqDY57Aia0TOQByoJhNt3icm4sfukp500hLH6RHOpFdV01NbECtAV7s0qKpQPibyRukQAwAmqJU3X/0, createdBy=f91f1928792, createdName=九九消寒, createdTime=Sat Mar 03 11:43:44 CST 2018, time=2018-03-03, status=1, ipAttribution=)]
    2018-07-22 yb6560
  5. [GetPortalCommentsPageByObjectIdResponse(id=1905705, encodeId=302b1905e055f, content=<a href='/topic/show?id=2ebd1e7981a' target=_blank style='color:#2F92EE;'>#trend#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17798, encryptionId=2ebd1e7981a, topicName=trend)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ced3193, createdName=freve, createdTime=Sun Apr 29 15:31:00 CST 2018, time=2018-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1908401, encodeId=5d07190840158, content=<a href='/topic/show?id=a8d0141605e' target=_blank style='color:#2F92EE;'>#pharma#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=62, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14160, encryptionId=a8d0141605e, topicName=pharma)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f634250, 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time=2018-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=292609, encodeId=50a129260958, content=优质资源.共同学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib06iaV3D9Tg5K0LqDY57Aia0TOQByoJhNt3icm4sfukp500hLH6RHOpFdV01NbECtAV7s0qKpQPibyRukQAwAmqJU3X/0, createdBy=f91f1928792, createdName=九九消寒, createdTime=Sat Mar 03 11:43:44 CST 2018, time=2018-03-03, status=1, ipAttribution=)]
  6. [GetPortalCommentsPageByObjectIdResponse(id=1905705, encodeId=302b1905e055f, content=<a href='/topic/show?id=2ebd1e7981a' target=_blank style='color:#2F92EE;'>#trend#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17798, encryptionId=2ebd1e7981a, topicName=trend)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ced3193, createdName=freve, createdTime=Sun Apr 29 15:31:00 CST 2018, time=2018-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1908401, encodeId=5d07190840158, content=<a href='/topic/show?id=a8d0141605e' target=_blank style='color:#2F92EE;'>#pharma#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=62, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14160, encryptionId=a8d0141605e, topicName=pharma)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f634250, 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time=2018-03-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=292609, encodeId=50a129260958, content=优质资源.共同学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib06iaV3D9Tg5K0LqDY57Aia0TOQByoJhNt3icm4sfukp500hLH6RHOpFdV01NbECtAV7s0qKpQPibyRukQAwAmqJU3X/0, createdBy=f91f1928792, createdName=九九消寒, createdTime=Sat Mar 03 11:43:44 CST 2018, time=2018-03-03, status=1, ipAttribution=)]
  7. [GetPortalCommentsPageByObjectIdResponse(id=1905705, encodeId=302b1905e055f, content=<a href='/topic/show?id=2ebd1e7981a' target=_blank style='color:#2F92EE;'>#trend#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=74, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=17798, encryptionId=2ebd1e7981a, topicName=trend)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ced3193, createdName=freve, createdTime=Sun Apr 29 15:31:00 CST 2018, time=2018-04-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1908401, encodeId=5d07190840158, content=<a href='/topic/show?id=a8d0141605e' target=_blank style='color:#2F92EE;'>#pharma#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=62, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14160, encryptionId=a8d0141605e, topicName=pharma)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=f634250, 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    2018-03-03 九九消寒

    优质资源.共同学习

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