Pharmacology and physiology of gastrointestinal enteroendocrine cells.
Pharmacology and physiology of gastrointestinal enteroendocrine cells.
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DOI：
10.1002/prp2.155
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发表时间：
2015-08
影响因子：
2.6
通讯作者：
Marshall F
中科院分区：
文献类型：
--
作者：
Mace OJ;Tehan B;Marshall F
胃肠道（GI）多肽由肠内分泌细胞（EEC）分泌。最近的技术进步以及内源性和合成配体的鉴定使得人们能够探索 EEC 的药理学和生理学。刺激激素分泌的肠内分泌信号通路涉及多种营养转运蛋白和 G 蛋白偶联受体 (GPCR)，它们在餐后肠道内的主要营养条件下同时激活。大多数研究调查 EEC 响应单一配体的激素分泌，尽管单个信号通路如何产生激素输出背后的机制已经得到很好的表征，但我们对这些信号通路如何汇聚以产生单一激素分泌反应的理解仍处于起步阶段。然而，营养物质和完整、部分或变构 GPCR 配体如何差异调节肠内分泌系统及其与肠和中枢神经系统的相互作用的图景正在开始显现。到目前为止，多种途径的激活是药物发现工作的基础，以利用肠内分泌系统的治疗潜力来模拟在接受 Roux-en-Y 胃手术的患者中观察到的表型变化。通常，肥胖患者的体重减轻约 30%，超过 80% 的肥胖糖尿病患者的糖尿病得到缓解。协同作用的靶向肠内分泌信号通路组合可能会表现出显着的、差异化的 EEC 分泌功效。此外，变构调节剂以其更高的选择性、自限活性和结构新颖性可能转化为更有前途的肠内分泌药物。加上偏向肠内分泌 GPCR 信号传导和/或激活多种不同信号传导途径的潜力，凸显了相当广泛的可用治疗可能性。在这里，我们回顾 EEC 系统的药理学和生理学。
Gastrointestinal (GI) polypeptides are secreted from enteroendocrine cells (EECs). Recent technical advances and the identification of endogenous and synthetic ligands have enabled exploration of the pharmacology and physiology of EECs. Enteroendocrine signaling pathways stimulating hormone secretion involve multiple nutrient transporters and G protein-coupled receptors (GPCRs), which are activated simultaneously under prevailing nutrient conditions in the intestine following a meal. The majority of studies investigate hormone secretion from EECs in response to single ligands and although the mechanisms behind how individual signaling pathways generate a hormonal output have been well characterized, our understanding of how these signaling pathways converge to generate a single hormone secretory response is still in its infancy. However, a picture is beginning to emerge of how nutrients and full, partial, or allosteric GPCR ligands differentially regulate the enteroendocrine system and its interaction with the enteric and central nervous system. So far, activation of multiple pathways underlies drug discovery efforts to harness the therapeutic potential of the enteroendocrine system to mimic the phenotypic changes observed in patients who have undergone Roux-en-Y gastric surgery. Typically obese patients exhibit ∼30% weight loss and greater than 80% of obese diabetics show remission of diabetes. Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy. Furthermore, allosteric modulators with their increased selectivity, self-limiting activity, and structural novelty may translate into more promising enteroendocrine drugs. Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available. Here, we review the pharmacology and physiology of the EEC system.