Hannig Gerhard, Tchernychev Boris, Kurtz Caroline B, Bryant Alexander P, Currie Mark G, Silos-Santiago Inmaculada
Department of Discovery Pharmacology, Ironwood Pharmaceuticals, Inc., Cambridge MA, USA.
Front Mol Neurosci. 2014 Apr 16;7:31. doi: 10.3389/fnmol.2014.00031. eCollection 2014.
Activation of guanylate cyclase-C (GC-C) expressed predominantly on intestinal epithelial cells by guanylin, uroguanylin or the closely related GC-C agonist peptide, linaclotide, stimulates generation, and release of cyclic guanosine-3',5'-monophosphate (cGMP). Evidence that the visceral analgesic effects of linaclotide are mediated by a novel, GC-C-dependent peripheral sensory mechanism was first demonstrated in animal models of visceral pain. Subsequent studies with uroguanylin or linaclotide have confirmed the activation of a GC-C/cGMP pathway leading to increased submucosal cGMP mediated by cGMP efflux pumps, which modulates intestinal nociceptor function resulting in peripheral analgesia. These effects can be reproduced by the addition of exogenous cGMP and support a role for GC-C/cGMP signaling in the regulation of visceral sensation, a physiological function that has not previously been linked to the GC-C/cGMP pathway. Notably, targeting the GC-C/cGMP pathway for treatment of gastrointestinal pain and abdominal sensory symptoms has now been validated in the clinic. In 2012, linaclotide was approved in the United States and European Union for the treatment of adult patients with irritable bowel syndrome with constipation.
鸟苷酸环化酶-C（GC-C）主要表达于肠道上皮细胞，鸟苷素、尿鸟苷素或密切相关的GC-C激动剂肽利那洛肽对其激活，可刺激环磷酸鸟苷（cGMP）的生成与释放。利那洛肽的内脏镇痛作用由一种新的、依赖GC-C的外周感觉机制介导，这一证据最早在动物内脏痛模型中得到证实。随后使用尿鸟苷素或利那洛肽的研究证实，GC-C/cGMP途径的激活导致由cGMP外排泵介导的黏膜下cGMP增加，从而调节肠道伤害性感受器功能，产生外周镇痛作用。添加外源性cGMP可重现这些效应，并支持GC-C/cGMP信号传导在调节内脏感觉中的作用，而此前这一生理功能与GC-C/cGMP途径并无关联。值得注意的是，针对GC-C/cGMP途径治疗胃肠道疼痛和腹部感觉症状目前已在临床上得到验证。2012年，利那洛肽在美国和欧盟被批准用于治疗患有便秘型肠易激综合征的成年患者。
