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Circulation：PPP1R3A缺陷促进房颤的发生发展！

2019-09-05 MedSci MedSci原创

PPP1R3A房颤RyR2PLN
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肌浆网钙(Ca2+)释放异常是房颤(AF)发病机制之一。2型ryanodine受体(RyR2)和磷脂(PLN)磷酸化水平提高可增强了AF的易感性，但其潜在机制仍不明确。蛋白磷酸酶1 (PP1)限制RyR2和PLN的稳态磷酸化。蛋白质组学分析在RyR2大分子通道复合物中发现了一个新的PP1调控亚基(PPP1R3A)，该亚基已被证明可介导PP1靶向PLN。现研究人员对PPP1R3A在心衰中的作用机制进

肌浆网钙(Ca2+)释放异常是房颤(AF)发病机制之一。2型ryanodine受体(RyR2)和磷脂(PLN)磷酸化水平提高可增强了AF的易感性，但其潜在机制仍不明确。蛋白磷酸酶1 (PP1)限制RyR2和PLN的稳态磷酸化。蛋白质组学分析在RyR2大分子通道复合物中发现了一个新的PP1调控亚基(PPP1R3A)，该亚基已被证明可介导PP1靶向PLN。现研究人员对PPP1R3A在心衰中的作用机制进行研究。

蛋白质组学表明PP1调控的PPP1R3A亚基是一种新型的RyR2结合伴侣，而且免疫共沉淀证实PPP1R3A与RyR2和PLN结合。复合体分析和SED成像显示，PLN存在于PPP1R3A-RyR2相互作用中，提示存在一个由RyR2和PLN/sarco/内质网钙ATPase-2a大分子复合物组成的既往未知的SR纳米结构域。该新型RyR2/PLN/sarco/内质网钙ATPase-2a复合物也被发现存在人类心房中。敲除小鼠的Ppp1r3a可破坏PP1与RyR2和PLN的结合。PP1靶向性降低与RyR2和PLN磷酸化水平升高、心房心肌细胞SR-Ca2+释放异常以及起搏诱导的房颤易感性增强有关。最后，PPP1R3A在阵发性和持续性(慢性)房颤患者的心房中的表达水平渐进性降低。

PPP1R3A是RyR2通道复合体中一个新的PP1调控子亚单位。降低PPP1R3A水平可影响PP1的靶向性，进而增强RyR2和PLN的磷酸化。缺乏PPP1R3A可促进SR-Ca2+的异常释放，增加小鼠对AF的易感性。基于PPP1R3A在房颤患者中表达下调，这该调控亚基或可成为房颤治疗的新靶点。

原始出处：

Katherina M. Alsina， et al.Loss of Protein Phosphatase 1 Regulatory Subunit PPP1R3A Promotes Atrial Fibrillation.Circulation. 2019；140：681–693

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    2019-12-10 wgsun

    #发生发展#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=2030751, encodeId=da822030e5114, content=<a href='/topic/show?id=71353e8964f' target=_blank style='color:#2F92EE;'>#发生发展#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=37896, encryptionId=71353e8964f, topicName=发生发展)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=346311, createdName=wgsun, createdTime=Tue Dec 10 12:53:00 CST 2019, time=2019-12-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1956491, encodeId=0562195649130, content=<a href='/topic/show?id=187714580c1' target=_blank style='color:#2F92EE;'>#PPP1R3A#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14580, encryptionId=187714580c1, topicName=PPP1R3A)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/DYAIOgq83eqcyT7aQIuoYGGYr889lEiaOVWSfvMQ4d2oxhTMlWzEr6lPmg6pxzCVvPScSZrne4JFSyyPRCOxllQ/132, createdBy=416a2500064, createdName=ms3323097325231039, createdTime=Fri Jul 24 03:53:00 CST 2020, time=2020-07-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1685543, encodeId=b5751685543ce, content=<a href='/topic/show?id=69571454573' target=_blank style='color:#2F92EE;'>#PP1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14545, encryptionId=69571454573, topicName=PP1)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4f1028217817, createdName=ms9651749636653578, createdTime=Fri May 08 05:53:00 CST 2020, time=2020-05-08, status=1, ipAttribution=)]
    2020-07-24 ms3323097325231039

    #PPP1R3A#

    0

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    2020-05-08 ms9651749636653578

    #PP1#

    0