Guanylate cyclase-C receptor activation: unexpected biology
Guanylate cyclase-C receptor activation: unexpected biology
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DOI：
10.1016/j.coph.2012.10.005
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发表时间：
2012-12-01
影响因子：
4
通讯作者：
Brierley, Stuart M.
中科院分区：
文献类型：
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作者：
Brierley, Stuart M.
鸟苷酸环化酶-C（GC-C）是一种由细菌热稳定肠毒素和内源性鸟苷素和尿鸟苷素激活的跨膜受体。GC-C在调节肠道液体和电解质稳态中起关键作用。最近发现的几种编码GC-C的基因GUCY 2C中的人类突变突出了这一点，这些突变导致GC-C功能的相应获得或丧失，从而对胃肠道功能产生深远影响。然而，最近的大量研究表明GC-C信号传导延伸到多种不同的附加功能。最近的临床前和临床研究表明，一种新型的GC-C激活肽，利那洛肽，可有效缓解慢性便秘和便秘为主的肠易激综合征患者的便秘和腹痛。越来越多的证据也表明GC-C在粘膜屏障功能、组织损伤和炎症中起保护作用，而GC-C信号传导是肠细胞增殖和凋亡的关键调节因子。最后，最近发现的肠外GC-C信号通路对调节食物摄入和与注意缺陷多动障碍相关的症状做出了新的贡献。因此，这些发现提供了GC-C表达及其相关突变作为疾病的潜在诊断标志物。它们还为胃肠道内外的GC-C信号传导提供了当前和未来的治疗潜力。
Guanylate cyclase-C (GC-C) is a transmembrane receptor activated by bacterial heat-stable enterotoxins and by the endogenous hormones guanylin and uroguanylin. GC-C plays key roles in the regulation of intestinal fluid and electrolyte homeostasis. This is highlighted by several recently identified human mutations in GUCY2C, the gene encoding GC-C, which leads to the respective gain or loss of function of GC-C, resulting in profound effects on gastrointestinal function. However, a wealth of recent studies indicates GC-C signalling extends to a multitude of diverse additional functions. Recent pre-clinical and clinical studies demonstrate a novel first-in-class GC-C activating peptide, Linaclotide, provides effective relief from constipation and abdominal pain in patients with chronic constipation and constipation-predominant Irritable Bowel Syndrome. Accumulating evidence also suggests GC-C plays protective roles in mucosal barrier function, tissue injury and inflammation, whilst GC-C signalling is a key regulator of intestinal cell proliferation and apoptosis. Finally, recently identified extra-intestinal GC-C signalling pathways make novel contributions to the regulation of food intake and symptoms associated with Attention Deficit Hyperactivity Disorder. Consequently, these findings provide GC-C expression and its associated mutations as potential diagnostic markers for disease. They also provide current and future therapeutic potential for GC-C signalling within and outside the gastrointestinal tract.