The molecular basis of the genesis of basal tone in internal anal sphincter.
The molecular basis of the genesis of basal tone in internal anal sphincter.
复制标题
肛门内括约肌基础张力发生的分子基础。
DOI：
10.1038/ncomms11358
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发表时间：
2016-04-22
影响因子：
16.6
通讯作者：
Zhu MS
中科院分区：
文献类型：
--
作者：
Zhang CH;Wang P;Liu DH;Chen CP;Zhao W;Chen X;Chen C;He WQ;Qiao YN;Tao T;Sun J;Peng YJ;Lu P;Zheng K;Craige SM;Lifshitz LM;Keaney JF Jr;Fogarty KE;ZhuGe R;Zhu MS
平滑肌括约肌表现出基础张力并控制内容物通过器官如胃肠道的通道;这种张力的丧失导致疾病如大便失禁。然而，这种音调背后的分子机制仍然未知。在这里，我们表明，删除肌球蛋白轻链激酶（MLCK）的平滑肌细胞从肛门内括约肌（IAS-SMCs）废除基础张力，损害排便。兰尼碱受体（RyR）、L型电压依赖性钙通道（VDCCs）或TMEM 16 A钙激活的Cl−通道的药理学调节可显著改变整体胞浆钙浓度（[Ca 2 +]i）和张力。IAS-SMC中的TMEM 16 A缺失消除了TMEM 16 A或VDCC的调节剂对RyR介导的整体[Ca 2 +]i升高的影响，并损害了张力和排便。因此，通过RyR-TMEM 16 A-VDCC信号传导模块由[Ca 2 +]i的整体升高引起的IAS-SMC中的MLCK激活设定基础张力。针对这个模块可能会导致新的治疗疾病，如大便失禁。 由肛门内括约肌（IAS）产生的基础张力的分子基础在很大程度上是未知的。在这里，作者表明，张力产生于平滑肌细胞中细胞内Ca 2+通过Ryanodine受体-TMEM 16 A-L-型Ca 2+通道-MLC激酶途径的整体上升，这表明IAS运动障碍的潜在治疗。
Smooth muscle sphincters exhibit basal tone and control passage of contents through organs such as the gastrointestinal tract; loss of this tone leads to disorders such as faecal incontinence. However, the molecular mechanisms underlying this tone remain unknown. Here, we show that deletion of myosin light-chain kinases (MLCK) in the smooth muscle cells from internal anal sphincter (IAS-SMCs) abolishes basal tone, impairing defecation. Pharmacological regulation of ryanodine receptors (RyRs), L-type voltage-dependent Ca2+ channels (VDCCs) or TMEM16A Ca2+-activated Cl− channels significantly changes global cytosolic Ca2+ concentration ([Ca2+]i) and the tone. TMEM16A deletion in IAS-SMCs abolishes the effects of modulators for TMEM16A or VDCCs on a RyR-mediated rise in global [Ca2+]i and impairs the tone and defecation. Hence, MLCK activation in IAS-SMCs caused by a global rise in [Ca2+]i via a RyR-TMEM16A-VDCC signalling module sets the basal tone. Targeting this module may lead to new treatments for diseases like faecal incontinence. The molecular basis of the basal tone generated by internal anal sphincters (IAS) is largely unknown. Here, the authors show that the tone arises from a global rise in intracellular Ca2+ in smooth muscle cells via a Ryanodine receptor-TMEM16A-L-type Ca2+ channel-MLC kinase pathway, suggesting a potential therapy for IAS motility disorders.