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SOCE mediated by STIM and Orai is essential for pacemaker activity in the interstitial cells of Cajal in the gastrointestinal tract
Science Signaling ( IF 7.3 ) Pub Date : 2018-06-12 , DOI: 10.1126/scisignal.aaq0918
Haifeng Zheng 1 , Bernard T. Drumm 1 , Scott Earley 2 , Tae Sik Sung 1 , Sang Don Koh 1 , Kenton M. Sanders 1
Affiliation  

Electrical pacemaker activity generates phasic contractions and motility patterns such as segmentation and peristalsis in the gastrointestinal tract. Pacemaker currents are generated in interstitial cells of Cajal (ICC), which release Ca2+ from intracellular stores that stimulates Ca2+-activated Cl channels (CaCCs) in the plasma membrane. Thus, Ca2+ stores must be maintained to sustain pacemaker activity. Store-operated Ca2+ entry (SOCE) facilitates the refilling of Ca2+ stores by a mechanism dependent upon interactions between STIM and Orai proteins. We investigated the role of SOCE in ICC pacemaker activity. Reintroduction of extracellular Ca2+ in store-depleted ICC resulted in CaCC activation. Blocking CaCCs revealed an inwardly rectifying current with properties of a Ca2+ release–activated current (ICRAC). An inhibitory peptide that interfered with the STIM-Orai interaction blocked ICRAC in HEK 293 cells expressing STIM1 and Orai1 and blocked spontaneous transient inward currents (STICs) and slow wave currents in ICC. STICs, which are fundamental pacemaker events in ICC, were blocked by an Orai antagonist. Imaging of Ca2+ transients linked to pacemaker activity in ICC in intact muscles showed that the Orai antagonist blocked Ca2+ transients in ICC. These data suggest that Ca2+ recovery through STIM-Orai interactions is necessary to maintain ICC pacemaker activity.



中文翻译:

STIM和Orai介导的SOCE对于胃肠道Cajal间质细胞中的起搏器活性至关重要

起搏器电活动在胃肠道中产生阶段性收缩和运动模式,例如分段和蠕动。起搏器电流在Cajal间(ICC)的间质细胞,其释放的Ca生成2+从细胞内贮存刺激的Ca 2+ -活化氯-在质膜中的通道(CaCCs)。因此,必须维持Ca 2+存储以维持起搏器活动。储存操作的Ca 2+进入(SOCE)通过依赖于STIM和Orai蛋白之间相互作用的机制促进Ca 2+储存的补充。我们调查了SOCE在ICC起搏器活动中的作用。重新引入细胞外Ca 2+储存耗尽的ICC中的CaCO3活化导致CaCC活化。阻断CaCCs可以显示一种向内整流电流,具有Ca 2+释放激活电流(I CRAC)的特性。干扰STIM-Orai相互作用的抑制肽阻止了表达STIM1和Orai1的HEK 293细胞中的I CRAC,并阻止了ICC中的自发瞬时内向电流(STIC)和慢波电流。SIC是ICC中的基本起搏器事件,但被Orai对手阻止。与完整肌肉中ICC的起搏器活动相关的Ca 2+瞬变的成像显示,Orai拮抗剂阻断了ICC中的Ca 2+瞬变。这些数据表明,Ca 2+ 通过STIM-Orai相互作用进行恢复对于维持ICC起搏器活动是必要的。

更新日期:2018-06-13
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