Ghrelin: a newly discovered ghrelin
Abstract Ghrelin is a newly discovered 28-amino acid ghrelin, an endogenous ligand for the growth hormone ho rmone secretagogue recep to r (GHS2R). When Ghrelin binds to its specific receptor (GHS2R), it produces a range of biological effects. Ghrelin has the biological function of stimulating the release of growth hormone in the anterior pituitary, increasing appetite, regulating energy metabolism, and promoting gastric acid secretion. The mechanism of action is still unclear.
Key words ghrelin; receptor; growth hormone; growth hormone releasing hormone; somatostatin
Ko jim a et al (1999) used immunohistochemistry to find a polypeptide consisting of 28 amino acids in gastric endocrine cells and arcuate nucleus of the hypothalamus in mice and humans, called Gh relin. It was first discovered that Ghrelin stimulates the secretion of growth hormone by binding to GHS2R, which proves that there is another regulation mechanism of growth hormone secretion in the human body that is different from the regulation mechanism of hypothalamic growth hormone releasing hormone (GHRH). Since then, people have found that Gh relin shows a diversity of regulation in regulating energy balance, increasing appetite, and promoting gastric acid secretion.
1. Structure and distribution of ghrelin
Ghrelin has a molecular weight of 3,300 Da and a particle diameter of 90 to 150 mm and is composed of 28 amino acids. The first 23 amino acid residues at the N-terminus of the Ghrelin precursor have a secretory signal peptide characteristic, from the glycine at position 24 to the 28 amino acid at position 52, the Gh relin sequence, and the C-terminal P2R of Gh2 relin (proline 2 The acid) structure is its recognition site. The composition and structure analysis of Gh relin showed that Ghrelin mainly has two molecular forms, namely, the N-terminal octanoylation and the N-terminal octanoylation of the third serine residue. The amino acid sequence of human Ghrelin is G2S2S2F2L 2S2P2E2H 2Q 2R 2V 2Q 2Q 2R 2K2E2 S2K2K2P2P2A 2K2L 2Q 2P2R , and the N-terminal octanoylation of the serine residue at position 3 plays an important role in its biological activity. After the N-terminal octanoylation, it is lost. Biological activity, in which the first four amino acid fragments (G2S2S2F) are the smallest active centers of Ghrelin . Ghrelin can be slightly different in different species structures, and human and mouse homology is 89%, and only amino acids at positions 11 and 12 are different. Ghrelin is widely distributed in a variety of tissues and organs, including the stomach, intestines, pancreas, kidneys, placenta, testes, hypothalamus, and pituitary gland. Among them, the highest concentration in gastric tissue is about 20% of the whole body, which is mainly secreted by X/A-like cells in the mucosal tissue of the stomach. Ghrelin levels were significantly reduced after gastrectomy .
2. Ghrelin receptor (GHS2R) and distribution
GHS2R has two subtypes, 1α and 1β. GHS2R1α contains 366 amino acids with 7 transmembrane domains, while GHS2R1β contains only 289 amino acids and 5 transmembrane domains. The secretory effect of GHS is mainly exerted by binding to 1α-type GHSR. Tannenbaaum et al (1998) found that Gh relin’s functional receptor GHS2R1α mRNA is mainly expressed in the pituitary gland, and is also expressed in the arcuate nucleus, ventromedial nucleus, and funnel nucleus of the hypothalamus, but in the thyroid, pancreas, spleen, adipose tissue and adrenal gland. Low, but not functional, GHS2R1β mRNA is widely expressed in tissues and organs.
Third, the biological effects of Ghrelin
(1) Promoting the secretion of growth hormone (GH) in vivo and in vitro
3 National Natural Science Foundation of China (30000120)
Experiments have confirmed that Ghrelin can significantly promote the secretion of GH. Intravenous injection of synthetic hGh relin was found to have a strong stimulating effect on the release of growth hormone in a dose-dependent manner. After giving Ghrelin at 0. 2, 1.0, and 5.0 mg / kg body weight, the peak height of growth hormone was 43. 3 6. 0, 81. 5 12. 7 , 107, respectively, 30 minutes after the injection. 0 10. 7 μg / ml, and there was no significant change in plasma luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) levels . The weaned pigs were perfused with 2 μg / kg body weight of hGh relin 3 times a day for 5 days. The results showed that hGhrelin significantly promoted the daily weight gain, growth hormone, insulin, cortisol level of weaned pigs compared with the control group. High, the difference was significant (P < 0.05) . Date et al (2000) found that intraventricular injection of Ghrelin in mice also stimulated the release of growth hormone in the anterior pituitary gland in a dose-dependent manner, reaching a peak in 15 to 20 minutes, and returning to the basal level in 60 minutes, but continued for 12 days. Only the first 6 days can promote the growth hormone growth, can not be sustained, indicating that Ghrelin only stimulates the release of growth hormone, but can not promote its synthesis. In vitro experiments have shown that Ghrelin can also significantly promote the release of growth hormone, but the effect is second to GHRH. Human hGh2 relin and murine rGh relin were added to the pituitary cells cultured in vitro, and 10 – 8 mo l /L and 10 – 7 were injected. </ br> </ br> < 0. 05 ) [ 5 ] . To shinaik et al (2001) also found that Ghrelin may also play a role in the differentiation of growth hormone cells. After binding of Gh relin to pituitary GHS2R, the pituitary-specific transcription factor (p it21) was expressed in a time- and dose-dependent manner, and growth hormone cells depended on p it21 for specific expression of growth hormone gene.
(2) Increasing appetite to regulate energy metabolism Ghrelin is injected into the brain and peripheral tissues of mice, which can strongly stimulate the appetite of mice, reduce energy consumption, increase body weight, and even increase the appetite of growth hormone deficiency . Anti-auxin immunoglobulin G can significantly inhibit appetite, and the antibody or antagonist of neuropeptide Y (NPY) and agouti2 related protin (A GRP) can block the appetite of Gh relin. Intraventricular or peripheral injection of Gh relin also increased the effect of feeding, and intraventricular injection of NPY
Progress in Physiological Sciences, Vol. 36, No. 3, 2005
Ghrelin inhibited the food intake of chicks in a dose-dependent manner, suggesting that the mechanism of action of Ghrelin on chickens may differ from that of mammals. Shiuya et al. (2002) found that the energy state of the body also had an effect on the expression of Ghrelin. The plasma Ghrelin concentration in patients with pre-meal, fasting and anorexia nervosa was higher than normal, and the plasma Ghrelin concentration in patients with glucose and simple obesity was lower than normal after dinner. In the absence of energy, the expression of Ghrelin mRNA in the fundus increased, the synthesis and release of Ghrelin increased, and the concentration of Ghrelin in the gastric vein and body vein increased. After the energy balance was restored, the above indexes returned to normal levels.
(C) the impact on the gastrointestinal tract M asuda et al (2000) found that the structure of Ghrelin is similar to motilin, Ghrelin in the peripheral or central involvement in the regulation of gastrointestinal physiological activities. Intravenous injection of 0. 8 ~ 2.0 μg / kg Ghrelin can cause a dose-dependent increase in gastric acid secretion, increased gastric frequency and amplitude. After vagus nerve cutting or atropine, it can block the increase of gastric acid secretion caused by Ghrelin, but it can not be blocked by histamine receptor (H22R) antagonist. It is speculated that this effect is exerted by vagus nerve and has nothing to do with GH increase. It was also found that perfusion of Ghrelin into the ventricle activates the solitary tract nucleus (NTS) and the dorsal nucleus of the vagus nerve (DMNV), which are important nucleus regulating the secretion of gastric acid in the brain. NTS accepts oral taste information and evoked nerve impulses, and commands DMNV; DMNV integrates visceral and central nervous sensory input, thereby transmitting integrated information to the stomach through the vagus nervous system, promoting gastric acid secretion .
Fourth, the mechanism of action of Ghrelin
After binding of GHRH to the receptor on the cell membrane, the AC / cAM P / PKA pathway is initiated, and adenylate cyclase (AC) first catalyzes the decomposition of ATP to generate cAM P as a second messenger, causing Ca2+ to enter the cell from the extracellular cAM P further specifically activates cAM P-dependent protein kinase A (PKA), which stimulates the synthesis and secretion of GH, while somatostatin (SS) inhibits GH secretion by blocking the synthesis of second messenger cAM P. The molecular mechanism by which Ghrelin promotes GH secretion is: Ghrelin binds to GHS2R and activates phospholipase C (PLC), which mediates the production of inositol 1,4,52 triphosphate (IP3) and diglyceride (DA G). IP promotes similar Ca2+ action from IP-sensitive Ca2+. Both N-containing PY neurons and arachnoid gene-related protein (AGRP) neurons in the appetite center of the hypothalamus can express GHS mRNA, and A GRP neurons in the arcuate nucleus can also express N PY mRNA. In NPY knockout rats, central injection of Ghrelin still caused an increase in food intake, indicating that Ghrelin promotes feeding is independent of NPY, and it is likely that A GRP regulates feeding behavior . Furuse et al (2001) found that the release of chicks into the cerebral ventricle pool, while DAG activation of PKC mediates Ca2+ from the extracellular into the intracellular, and thus caused a rapid increase in intracellular Ca2+ concentration, thereby promoting Release of GH. W u et al (1996) found in sheep in vitro that Ghrelin can activate adenylate cyclase in sheep growth hormone cells, increase the concentration of cAM P, initiate AC / cAM P / PKA pathway to promote GH secretion, and Gh relin and
GHRH acts synergistically on sheep GH cells and has a synergistic effect on GH secretion. In addition, antagonists of PKC can only partially reduce the ability of GHRP22 to promote GH secretion. The characteristics of these two GHS indicate that GHS2R may have other subtypes in addition to the αI and βI subtypes, which play a broad and important role.
5. Physiological and pathological significance
The study on the physiological effects of Ghrelin and its mechanism of action can help people understand the regulation of the growth axis of the body. The mechanism of action of Gh rlin and GH2RH and SS is different. Ghrelin’s changes in certain diseases are important for the diagnosis and treatment of its application. The combination of GHRH and Ghrlin has a strong stimulation of GH secretion and may have great application prospects in the diagnosis of certain GH-deficient diseases. Some GH-deficient diseases respond to GHRH, while others respond only to GHS2R. After prolonged consumption of critically ill patients, the decline in GH may result from a decrease in Ghrelin, a decrease in GH synthesis, and an increase in SS, which is given during treatment.
GHRH or Gh relin may help the patient recover.
Ghrelin is a newly discovered brain-gut peptide in human body, and its pathophysiological significance is not fully understood. Because it is related to nutropin aq nuspin growth hormone and energy balance and gastric acid secretion, it is speculated that it may be related to human growth, the development of obesity, ulcer disease and even tumors [9, 10]. At present, obesity has become a killer of human health, and the regulation of food intake is an important factor in maintaining weight stability. Therefore, if you can develop drugs that inhibit the secretion of growth hormone, it is undoubtedly a boon to patients such as obesity.
Is the difference between the likes and dislikes determined by the time difference?
Is it true that people’s likes and dislikes of things are absolute? People know that pain itself is painful, but correspondingly, pain can be alleviated and pleasant. Is this effect caused by “hardship” the same as “Ganlai”, which can also make people yearn for it? Tan imo to et al. at Wrzburg University in Germany confirmed the above conjecture. They combined the electric shock, the painful stimulus of the fruit fly, with an odor that did not attract the fruit fly to form a conditioned reflex. But unlike the past, they let the smell appear in different time before and after the shock. The results are very surprising: the combination with electric shock does not always allow fruit flies to learn to avoid these odors. They found that only the odor was given within 3 to 23 s before the electric shock, so that the fruit flies could avoid the smell; if the smell appeared 32 to 42 s after the electric shock, the fruit flies would not only avoid it, but would choose to approach the smell. The only difference is that the effective avoidance window is closer to the stimulus than the attracting window, and the avoidance effect is far stronger than the attracting effect. According to the Haibu learning law extended by Pu Muming and Yang Dan, this phenomenon also occurs between neurons before and after the synapse, that is, if the presynaptic neurons are within a certain time window before the postsynaptic neurons The issuance of action potentials can cause long-term potentiation; conversely, if the presynaptic release falls within a certain time window after post-synaptic release, long-term inhibition will be triggered. If the neurons before and after the synapse are repeatedly discharged, their mutual influence will have a superposition effect. According to the author’s hypothesis, the synaptic two-way plasticity produced by the intersection of electric shock and odor on the way up may be the basis for achieving the above behavioral response. The authors also believe that the study of the reward effect mechanism after negative stimulation will help people understand the different behaviors of patients during trauma recovery.