The ryanodine receptor mediates early zymogen activation in pancreatitis
The ryanodine receptor mediates early zymogen activation in pancreatitis
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DOI：
10.1073/pnas.0503215102
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发表时间：
2005-10-04
影响因子：
11.1
通讯作者：
Gorelick, FS
中科院分区：
文献类型：
--
作者：
Husain, SZ;Prasad, P;Gorelick, FS
急性胰腺炎的特征是胰腺腺泡细胞内酶原的病理性激活。该过程需要从未定义的细胞内存储的胞质Ca2+的上升。我们假设酶原激活是由兰尼碱受体（RYR）调节的Ca 2+释放介导的，因为早期酶原激活发生在一个核上区室，该区室与RYR一起分布。Ca2+信号在基底外侧，但不是顶端，在超生理激动剂刺激期间观察到的腺泡细胞区域依赖于RYR Ca2+释放。抑制RYR或耗竭RYR敏感的Ca2+池各自降低了分离腺泡细胞中的病理性酶原激活，但两种治疗均不影响淀粉酶分泌。RYR的抑制也抑制了酶原在体内的活化。我们建议，Ca2+释放从RYR介导酶原激活，但不酶分泌。这些发现意味着RYR在急性胰腺炎中发挥作用。
Acute pancreatitis is characterized by the pathologic activation of zymogens within pancreatic acinar cells. The process requires a rise in cytosolic Ca2+ from undefined intracellular stores. We hypothesized that zymogen activation is mediated by ryanodine receptor (RYR)-regulated Ca2+ release, because early zymogen activation takes place in a supranuclear compartment that overlaps-in distribution with the RYR. Ca2+ signals in the basolateral, but not apical, region of acinar cells observed during supraphysiologic agonist stimulation were dependent on RYR Ca2+ release. Inhibition of RYR or depletion of RYR-sensitive Ca2+ pools each reduced pathologic zymogen activation in isolated acinar cells, but neither treatment affected amylase secretion. Inhibition of RYR also inhibited zymogen activation in vivo. We propose that Ca2+ release from the RYR mediates zymogen activation but not enzyme secretion. The findings imply a role for the RYR in acute pancreatitis.