浅谈脑—肠肽

脑-肠肽是指体内那些既存在于脑,也存在于胃肠道的,以双重分布为特点的调节肽。脑-肠肽的概念出现于本世纪70年代末,它提示在神经系统和胃肠之间、神经系统和激素之间存在着相互关联、相互协调的密切联系,因而是胃肠激素研究中的一个重大突破。     

胃肠内分泌学的新进展

本文对胃肠内分泌学的特点以及胃肠激素和肽类的化学、生理学的新进展作了简要的介绍。胃肠内分泌学近十余年来进展迅速,一些老激素的分离、提纯、阐明化学结构和人工合成,一些新激素和肽类的发现,使这一部分科学的面貌为之一新。胃肠激素和肽类是由个别地散处于胃肠道粘膜上皮细胞之间的内分泌细胞所分泌。由于胃肠道粘膜的面积特别大,胃肠内分泌细胞的总数超过机体所有其它内分泌细胞的总和,因而消化道粘膜被认为是机体内最大最复杂的内分泌器官。另一值得注意的现象是:有些存在于神经系统中的肽类,也在消化道内发现;而原先在消化道内发现的,现在也在神经系统中找到。此现象的生理意义,尚有待进一步明确。     

胃肠激素与肥胖关系的研究进展

胃肠激素(gastrointestinal hormone)是一类性质不同的具有激素或类激素功能的多肽,这些肽可将胃肠道的信号传递到食欲相关的脑区进行整合,然后沿神经纤维传递到神经末梢进行释放,从而调节细胞活动。胃肠激素在机体的能量稳态平衡中发挥重要调节作用。膳食中三种产能营养素的比例失调或不良的饮食行为会导致机体能量稳态调节失衡。目前研究认为,胃肠激素可能是有效治疗肥胖的新型潜在靶点,但其作用机制尚不清楚。因此,本文对ghrelin、胆囊收缩素(Cholecystokinin,CCK)和胰高血糖素样肽-1(Glucagon peptide-1,GLP-1)三种胃肠激素与肥胖的发生及发展之间关系进行综述。     

Ghrelin与疼痛研究进展

Ghrelin为1999年从大鼠胃粘膜及下丘脑中发现的一种生长激素促分泌素受体(growth hor-mone secretagogue receptor,GHS-Rs)的天然配体,由28个氨基酸残基组成。Ghrelin广泛分布于机体的多个组织器官,如下丘脑、垂体、胃肠道、胰腺、心脏、性腺等。Ghrelin与其受体结合后,具有促进生长激素的释放、增加摄食、刺激胃蠕动和胃酸分泌,改善心血管等多种生物学作用。近年来有研究表明,Ghrelin在中枢神经系统具有广泛分布,并且具有镇痛作用,其主要通过调节与疼痛有关的系统和抑制促炎细胞因子的分泌进而缓解疼痛。现将Ghrelin在疼痛方面的研究做一综述。     

Ghrelin与生殖系统研究进展

Ghrelin是1999年发现的生长激素促分泌素受体(growth hormone secretagogue receptor,GHS-R)的天然配体,由28个氨基酸残基组成.除具有促进生长激素的释放、增加摄食、刺激胃蠕动和胃酸分泌,尚有其它许多功能.近年来发现Ghrelin及其受体在生殖系统也广泛分布,提示Ghrelin对生殖系统也具有重要的调节作用,进一步的研究发现Ghrelin具有调节生殖激素黄体生成素、催乳素、雌二醇和孕酮的分泌,促进颗粒细胞的增殖等作用.本文就Ghrelin在生殖系统的研究进展做如下综述.     

甘丙肽家族及其受体的功能

甘丙肽家族包含甘丙肽(galanin)、甘丙肽信息相关肽(galanin-message-associated peptide,GMAP)、甘丙肽样肽(galanin-like peptide,GALP)和alarin。目前已经克隆了三种甘丙肽受体,分别是GalR1、GalR2、GalR3,它们都是G蛋白偶联受体。三种受体具有不同的分布特征,介导不同的生理过程。甘丙肽及其受体在生物体内中枢神经系统和外周神经系统中分布广泛,参与学习和记忆、焦虑行为、痛觉调节、摄食活动、渗透平衡、神经损伤修复和神经保护、胃肠道活动以及皮肤炎症处理等多种生理过程。这些生理功能提示甘丙肽及其受体可能在多种疾病的病理过程中发挥着潜在的作用,如阿尔茨海默氏病、癫痫、酗酒、糖尿病、神经性疼痛、抑郁症和癌症。     

唾液腺能够产生Ghrelin

Ghrelin是最初在胃内分泌细胞中发现的脑肠肽,是生长激素促分泌受体（GHS-R）的内源性配体。近年来的研究证明,除胃肠道外,两栖类动物的下丘脑、心脏、胰腺、肺、胎盘都能产生ghrelin。Ghrelin由28个氨基酸组成,其N端第3位n-辛酰化的丝氨酸是ghrelin与其受体结合并发挥生物学活性的关键部位。Ghrelin主要的生理功能是促进生长激素释放,促进摄食和调节能量代谢。Ghrelin可以作用于胃肠道,     

卵巢激素调节大鼠胃运动及感觉功能的机制

女性患者在孕期及月经周期的黄体期常有腹痛、腹胀及腹泻等胃肠道功能紊乱的症状.本文探讨雌二醇（estradiol benzoate,EB）和孕酮（progesterone,P4）对卵巢切除大鼠血浆胆囊收缩素（cholecystokinin,CCK）及胃组织内胆囊收缩素受体A（CCKA）、血浆降钙素基因相关肽（calcitonin gene-related peptide,CGRP）及胃组织内其受体表达水平的影响,以期阐明卵巢激素调节胃肠道运动及感觉功能的机制.给予卵巢切除大鼠EB和P4替代治疗,用放射免疫分析法测定血浆CCK、CGRP的浓度,用Western blot法检测胃组织内CCKA受体的表达量,用125I-CGRP放射配体结合分析法测定胃组织内CGRP受体的表达量.EB可以升高血浆CCK的浓度,同时引起胃组织内CCKA受体表达增高.P4对血浆CCK的浓度以及胃组织内CCKA受体的表达无明显影响,但P4可以升高血浆CGRP的浓度,上调胃组织内CGRP受体的活性.EB、P4联合作用升高血浆CCK、CGRP的浓度,增加胃内CCKA、CGRP受体的表达.因此EB通过促进CCK的分泌以及上调胃内CCKA受体的表达,抑制胃排空;而P4可以通过增加CGRP的释放上调胃内CGRP受体的活性,从而增加肠神经系统对外来刺激的敏感性.结果提示,可以利用CCKA、CGRP受体的拈抗剂治疗女性患者中与月经周期有密切关系的胃肠道功能紊乱症状,如腹胀、早饱、腹痛等.     

Ghrelin:一种新发现的生长激素释放肽

Ghrelin是一种新发现的含有28个氨基酸的生长激素释放肽,为生长激素促分泌素受体(growthhormonesecretagoguereceptor,GHSR)的内源性配体。当Ghrelin与其特异性受体(GHSR)结合后会产生一系列生物学效应。Ghrelin具有刺激垂体前叶释放生长激素、增加食欲、调节能量代谢平衡,以及促进胃酸分泌等生物学功能,其作用机制目前尚不清楚。     

降钙素基因相关肽受体研究的新进展

降钙素基因相关肽(calcitonin gene-related peptide,CGRP)是一种神经肽,它由37个氨基酸残基组成。CGRP通过激活细胞膜上的CGRP受体参与循环系统、神经系统等功能的调节,特别是CGRP在血管舒张以及偏头痛中发挥着重要的作用。过去认为CGRP受体是一种经典的G蛋白偶联受体,具有G蛋白偶联受体的结构特性。近年来发现,与经典的G蛋白偶联受体不同,具有生物活性的CGRP受体由降钙素受体样受体(calcitonin receptor-like receptor,CLR)、受体活性修饰蛋白-1(receptor activity modifying protein,RAMP1)和受体组成蛋白(receptor component protein,RCP)组成,CGRP受体的这些不同组分在跨膜信号转导中分别发挥不同的作用。RAMP参与多种G蛋白偶联受体的组成,在G蛋白偶联受体的表型及功能调节等方面具有重要的作用。所以,RAMP的发现修正了有关G蛋白偶联受体的基本概念和理论。目前对CLR,RAMP以及RCP在CGRP受体激活和信号转导中作用的研究已经有了很大的进展。深入研究RAMP的胞外N末端和RAMP的单跨膜区域如何协同CLR以识别并结合相应的配体,以及G蛋白与RCP之间怎样相互作用,都将为有关G蛋白偶联受体的理论提供新的内容。本文将综述CGRP受体各组分的结构和功能,以及它们之间的相互作用对CGRP受体功能的影响。     

Ghrelin acts in the central nervous system to stimulate gastric acid secretion

Ghrelin is a novel acylated peptide that functions in the regulation of growth hormone release and energy metabolism. It was isolated from rat stomach as an endogenous ligand for growth hormone secretagogue receptor. Ghrelin is also localized in the arcuate nucleus of rat hypothalamus. Intracerebroventricular (ICV) administration increases food intake and body weight. We examined the effect of ghrelin on gastric acid secretion in urethane-anesthetized rats and found that ICV administration of ghrelin increased gastric acid output in a dose-dependent manner. Vagotomy and administration of atropine abolished the gastric acid secretion induced by ghrelin. ICV administration of ghrelin also induced c-fos expression in the neurons of the nucleus of the solitary tract and the dorsomotor nucleus of the vagus, which are key sites in the central nervous system for regulation of gastric acid secretion. Our results suggest that ghrelin participates in the central regulation of gastric acid secretion by activating the vagus system.     

Intraventricular calcitonin gene-related peptide inhibits gastric acid secretion

Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide recently demonstrated to be a peptide expressed by the calcitonin gene in the rat central nervous system. Intracerebroventricular administration of CGRP in pylorus ligated rats resulted in a dose dependent suppression of gastric acid secretion. This effect was also present in acutely vagotomized rats. In addition, CGRP inhibited the stimulation of gastric acid secretion by thyrotropin releasing hormone. CGRP was considerably less potent in its effect on gastric acid than calcitonin, a well known central inhibitor of gastric acid secretion in the rat. This study suggests that CGRP may be a factor in the central regulation of gastric acid secretion in the rat.     

Ghrelin: a metabolic signal affecting the reproductive system

Ghrelin, an acylated 28 amino acid gastric peptide, was isolated from the stomach as an endogenous ligand for growth hormone (GH) secretagogue receptor in 1999. Circulating ghrelin is mainly produced by specific cells in the stomach's oxyntic glands. Ghrelin potently stimulates GH release and food intake and exhibits diverse effects, including ones on glucose metabolism and on secretion and motility of the gastrointestinal tract. Besides these effects on food intake and energy homeostasis, ghrelin is also involved in controlling reproductive functions, and a role for it as a novel regulator of the hypothalamic-pituitary gonadal axis is clearly emerging.We review recent ghrelin research with emphasis on its roles in the reproductive axis.     

Role of ghrelin in the regulation of gastric acid secretion involving nitrergic mechanisms in rats

Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), has been identified in the rat and human gastrointestinal tract. Ghrelin has been proposed to play a role in gastric acid secretion. Nitric oxide (NO) was shown as a mediator in the mechanism of ghrelin action on gastric acid secretory function. However, there is a little knowledge about this topic. We have investigated the role of ghrelin in gastric acid secretion and the role of NO as a mediator. Wistar albino rats were used in this study. The pyloric sphincter was ligated through a small midline incision. By the time, saline (0.5 ml, iv) was injected to the control group, ghrelin (20 microg/kg, iv) was injected to the first experimental group, ghrelin (20 microg/kg, iv) + L-NAME (70 mg/kg, sc) was injected to the second group and L-NAME (70 mg/kg, sc) was administered to the third group. The rats were killed 3 h after pylorus ligation; gastric acid secretion, mucus content and plasma nitrite levels were measured. Exogenous ghrelin administration increased gastric acid output, mucus content and total plasma nitrite levels, while these effects of ghrelin were inhibited by applying L-NAME. We can conclude that ghrelin participates in the regulation of gastric acid secretion through NO as a mediator.     

The effects of thyrotropin releasing hormone (TRH) on the gastrointestinal tract.

Thyrotropin-releasing hormone (TRH) immunoreactivity is distributed throughout the gastrointestinal tract and the pancreas. We have studied the effect of TRH on several gastrointestinal functions in intact, unanesthetized dogs. Intravenous TRH stimulated gastric action potentials (p<0.01) and transiently inhibited tetragastrin-stimulated gastric acid secretion (p<0.05). TRH had no effect on basal or secretin-stimulated pancreatic exocrine secretion. TRH did not alter water absorption in dogs with Thiry-Vella loops constructed from proximal jejunum.     

Two new peptides to improve post-operative gastric ileus in dog

Peptides can influence gastrointestinal motility, and from data obtained earlier in rats, we hypothesized that MTL-RP/Ghrelin, as well as CGRP receptor antagonist 8-37, could improve gastric post-operative ileus in dog. Dogs submitted to laparotomy were perfused with or saline or CGRP 8-37 or MTL-RP/Ghrelin on days 1-4 post-operatively while gastric emptying was estimated by measuring the postprandial increase in plasma acetaminophen ingested with a meal. As expected, in saline-treated animals the gastric emptying function was impaired post-operatively. The total amount of acetaminophen emptied (AUC over 150 min) on post-operative days 1-4 reached respectively 31+/-5%, 65+/-8%, 60+/-8% and 62+/-8% of the normal emptying capacity. CGRP antagonist increased the total emptying of acetaminophen to 52+/-5% on day 1, 95+/-2% on day 2 and 103+/-3% (P<0.05) on day 3. The delayed emptying of acetaminophen seen post-operatively in saline-treated animals could be completely reversed by MTL-RP/Ghrelin (P<0.01) whether it was given at 100 microg/kg on day 2 (102+/-7% of the normal emptying capacity), 4 microg/kg on day 3 (106+/-7%) or 20 microg/kg on day 4 (132+/-8%). As found earlier in rodents, CGRP receptor antagonist 8-37 as well as MTL-RP/Ghrelin are potent prokinetics to improve post-operative gastric ileus in dog.     

Phylogenetic Distribution and Function of the Hypophysiotropic Hormones of the Hypothalamus

SYNOPSIS. Following the isolation, synthesis and subsequentdevelopment of specific and sensitive radioimmunoassays forthe hypothalamic hormones thyrotropin-releasing hormone (TRH),luteinizing hormone-releasing hormone (LH-RH) and growth hormonerelease-inhibiting hormone (somatostatin), it was recognizedthat these peptides were not localized solely in the hypothalamus,but were widely distributed throughout the mammalian nervoussystem. Somatostatin occurs outside the nervous system altogether,being located in the gastrointestinal tract of vertebrates whereit may have a physiologic role in the secretion of gastrointestinalhormones. TRH, also, has been located outside the nervous system,occurring in large quantities in the skin of Rana species whereit may be of physiologic importance in skin function. This tripeptideis found throughout the nervous system of vertebrate and invertebratespecies in situations where it has no pituitary-thyroid function.Thesepeptides are present in brain synaptosomes and enzymatic degradingsystems have been recognized for each in brain tissue. For TRH,specific receptors and synthesizing activity have been detectedoutside the hypothalamic-pituitary system. The anatomic location,phylogenetic distribution, neurophysiologic and behavioral effectsstrongly support a role for these substances in neuronal regulation,apart from control of pituitary secretion. Evolutionary studies,especially of TRH, suggest that their primary function may beas neurotransmitters.     

生长抑素的生理作用及其与哺乳动物冬眠启动的关系

生长抑素(somatostatin, SS)是一种具有抑制性作用的脑肠肽,在哺乳动物的中枢神经系统及消化系统中广泛分布,具有抑制多种垂体激素的分泌、维持胃肠道功能等重要作用。冬眠是一种低体温和低代谢状态,以全身多器官功能暂时"休止"为特征,依据生长抑素特殊的"刹车"作用,推测其与冬眠启动过程相关。本文综述了生长抑素的生理作用及其与哺乳动物冬眠启动的关系。     

PI3K p110α/Akt signaling negatively regulates secretion of the intestinal peptide neurotensin through interference of granule transport

Neurotensin (NT), an intestinal peptide secreted from N cells in the small bowel, regulates a variety of physiological functions of the gastrointestinal tract, including secretion, gut motility, and intestinal growth. The class IA phosphatidylinositol 3-kinase (PI3K) family, which comprised of p110 catalytic (α, β and δ) and p85 regulatory subunits, has been implicated in the regulation of hormone secretion from endocrine cells. However, the underlying mechanisms remain poorly understood. In particular, the role of PI3K in intestinal peptide secretion is not known. Here, we show that PI3K catalytic subunit, p110α, negatively regulates NT secretion in vitro and in vivo. We demonstrate that inhibition of p110α, but not p110β, induces NT release in BON, a human endocrine cell line, which expresses NT mRNA and produces NT peptide in a manner analogous to N cells, and QGP-1, a pancreatic endocrine cell line that produces NT peptide. In contrast, overexpression of p110α decreases NT secretion. Consistently, p110α-inhibition increases plasma NT levels in mice. To further delineate the mechanisms contributing to this effect, we demonstrate that inhibition of p110α increases NT granule trafficking by up-regulating α-tubulin acetylation; NT secretion is prevented by overexpression of HDAC6, an α-tubulin deacetylase. Moreover, ras-related protein Rab27A (a small G protein) and kinase D-interacting substrate of 220 kDa (Kidins220), which are associated with NT granules, play a negative and positive role, respectively, in p110α-inhibition-induced NT secretion. Our findings identify the critical role and novel mechanisms for the PI3K signaling pathway in the control of intestinal hormone granule transport and release.     

Renal function during bovine neurotensin infusion in man

The peptide hormone neurotensin (NT) is found mainly in gut endocrine cells of the ileum, but has also been identified as a putative neurotransmitter in the central and peripheral nervous systems. It may have a dual role as a circulating gastrointestinal hormone and peripheral neurotransmitter. Its predominant effects are to reduce oesophageal sphincter tone, inhibit gastric secretion and emptying and inhibit intestinal motility, but stimulate intestinal and pancreatic exocrine secretion; NT-like immunoreactivity has been found in kidney and therefore NT may influence renal function. When infused i.v. in rabbits it causes antinatriuresis. We have studied its renal effects in 11 healthy males by i.v. infusion under conditions of altered dietary sodium. Postprandial circulating neurotensin levels were reproduced by infusion. There were no consistent systemic or renal haemodynamic effects. Plasma electrolytes and renin did not change. Only renal chloride excretion changed significantly, falling by ca. 30%, and recovering after infusion. There is no evidence for a specific renal tubular chloride transport mechanism, but coupled cotransport, Na+:K+:2CI-, may be hormonally regulated. NT might stimulate this process and contribute to the renal response to changes in dietary composition, especially sodium intake.