NMR solution structure of motilin in phospholipid bicellar solution.
|Locus||Chr. 6 p21.3-p21.2|
Structure of motilin in isotropic phospholipid bicellar solution.
Motilin is secreted by endocrine M cells (these are not the same M cells that are in Peyer's patches) that are numerous in crypts of the small intestine, especially in the duodenum and jejunum. It is released into the general circulation in humans at about 100-min intervals during the inter-digestive state and is the most important factor in controlling the inter-digestive migrating contractions; and it also stimulates endogenous release of the endocrine pancreas. Based on amino acid sequence, motilin is unrelated to other hormones. Because of its ability to stimulate gastric activity, it was named "motilin". Apart from in humans, motilin receptors are found in the gastrointestinal tracts of pigs, rats, cows, and cats, and in the central nervous system of rabbits.
Motilin was discovered by J.C. Brown when he introduced alkaline solution into duodena of dogs, which caused strong gastric contractions. Brown et al. predicted that alkali could either release stimulus to activate motor activity or prevent the secretion of inhibitory hormone. They isolated a polypeptide as a by-product from purification of secretin on carboxymethyl cellulose. They named this polypeptide “Motilin.”
Motilin has 22 amino acids and molecular weight of 2698. In extract from human gut and plasma, there are two basic forms of motilin. The first molecular form is the polypeptide of 22 amino acids. The second form, on the other hand, is larger and contains the same 22 amino acids as the first form but includes an additional carboxyl-terminus end.
The structure and dynamics of the gastrointestinal peptide hormone motilin have been studied in the presence of isotropic q = 0.5 phospholipid bicelles. The NMR solution structure of the peptide in acidic bicelle solution was determined from 203 NOE-derived distance constraints and six backbone torsion angle constraints. Dynamic properties for the 13Cα→1H vector in Leu-10 were determined for motilin specifically labeled with 13C at this position by analysis of multiple-field relaxation data. The structure reveals an ordered alpha-helical conformation between Glu-9 and Lys-20. The N-terminus is also well structured with a turn resembling that of a classical beta-turn. The 13C dynamics clearly show that motilin tumbles slowly in solution, with a correlation time characteristic of a large object.
Control of motilin secretion is largely unknown, although some studies suggest that an alkaline pH in the duodenum stimulates its release. It is interesting to note, however, that at low pH it inhibits gastric motor activity, whereas at high pH it has a stimulatory effect. Some studies in dogs have shown that motilin is released during fasting or interdigestive period, and intake of food during this period can prevent the secretion of motilin. Intravenous injection of glucose, which increases the release of insulin, is also found to inhibit cyclic elevation of plasma motilin. Other studies on dogs have also suggested that motilin acted as endogenous ligand in positive feedback mechanism to stimulate the release of more motilin.
The main function of motilin is to increase the migrating myoelectric complex component of gastrointestinal motility and stimulate the production of pepsin. Motilin is also called "housekeeper of the gut" because it improves peristalsis in the small intestine and clears out the gut to prepare for the next meal. A high level of motilin secreted between meals into the blood stimulates the contraction of the fundus and antrum and accelerates gastric emptying. It then contracts the gallbladder and increases the squeeze pressure of the lower esophageal sphincter. Other functions of motilin include increasing the release of pancreatic polypeptide and somatostatin
Erythromycin and related antibiotics act as non-peptide motilin agonists, and are sometimes used for their ability to stimulate gastrointestinal motility. Administration of a low dose of erythromycin will induce peristalsis, which provides additional support for the conclusion that motilin secretion triggers this pattern of gastrointestinal motility, rather than results from it. However, some of erythromycin’s properties, including antibiotic activity, are not appropriate for a drug designed for chronic use over a patient's lifetime.
New motilin agonists are erythromycin-based; however, it may be that this class of drugs becomes redundant. Growth hormone secretagogue receptors share 52% of their DNA with motilin receptors, and agonists of these receptors, termed ghrelins, can bring about similar effects to motilin agonists.
This domain is also found in ghrelin, a growth hormone secretagogue synthesised by endocrine cells in the stomach. Ghrelin stimulates growth hormone secretagogue receptors in the pituitary. These receptors are distinct from the growth hormone-releasing hormone receptors, and, thus, provide a means of controlling pituitary growth hormone release by the gastrointestinal system. Erythromycin has an advantage over metoclopramide in gastric emptying due to lack of central nervous system side-effects. It is not approved by FDA to use for gastric emptying. For short duration for patients with diabetes and for those that must clear the stomach for any procedure, it may be used based on the physician's discretion with full understanding that it is not approved by FDA for this use.
- PDB 1lbj; Andersson A, Mäler L (October 2002). "NMR solution structure and dynamics of motilin in isotropic phospholipid bicellar solution". J. Biomol. NMR 24 (2): 103–12. doi:10.1023/A:1020902915969. PMID 12495026.
- Daikh DI, Douglass JO, Adelman JP (October 1989). "Structure and expression of the human motilin gene". DNA 8 (8): 615–21. doi:10.1089/dna.1989.8.615. PMID 2574660.
- Poitras P, Peeters TL (February 2008). "Motilin". Current Opinion in Endocrinology, Diabetes and Obesity 15 (1): 54–7. doi:10.1097/MED.0b013e3282f370af. PMID 18185063.
- Itoh Z (1997). "Motilin and clinical application". Peptides 18 (4): 593–608. doi:10.1016/S0196-9781(96)00333-6. PMID 9210180.
- Brown JC, Cook MA, Dryburgh JR (May 1973). "Motilin, a gastric motor activity stimulating polypeptide: the complete amino acid sequence". Canadian journal of biochemistry 51 (5): 533–7. doi:10.1139/o73-066. PMID 4706833.
- DeGroot, Leslie Jacob (1989). J.E. McGuigan, ed. Endocrinology. Philadelphia: Saunders. p. 2748. ISBN 0-7216-2888-5.
- Williams, Robert L. (1981). Textbook of endocrinology (6th ed.). Philadelphia: Saunders. pp. 704–705. ISBN 0-7216-9398-9.
- Itoh Z, Takeuchi S, Aizawa I, Mori K, Taminato T, Seino Y, Imura H, Yanaihara N. (October 1978). "Changes in plasma motilin concentration and gastrointestinal contractile activity in conscious dogs". The American journal of digestive diseases 23 (10): 929–35. doi:10.1007/BF01072469. PMID 717352.
- Lemoyne M, Wassef R, Tassé D, Trudel L, Poitras P (September 1984). "Motilin and the vagus in dogs". Canadian Journal of Physiology and Pharmacology 62 (9): 1092–6. doi:10.1139/y84-182. PMID 6388765.
- Hall KE, Greenberg GR, El-Sharkawy TY, Diamant NE (July 1984). "Relationship between porcine motilin-induced migrating motor complex-like activity, vagal integrity, and endogenous motilin release in dogs". Gastroenterology 87 (1): 76–85. PMID 6724277.
- Frohman, Lawrence A.; Felig, Philip (2001). P. K. Ghosh and T. M. O’Dorisio, ed. Endocrinology & metabolism. New York: McGraw-Hill, Medical Pub. Div. p. 1330. ISBN 0-07-022001-8.
- Kangawa K, Matsuo H, Kojima M, Hosoda H (2001). "Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor". Trends Endocrinol. Metab. 12 (3): 118–122. doi:10.1016/S1043-2760(00)00362-3. PMID 11306336.
- Motilin at the US National Library of Medicine Medical Subject Headings (MeSH)
- Physiology at MCG 6/6ch2/s6ch2_26