Motilin

Last updated

Motilin/ghrelin
PDB 1lbj EBI.jpg
Structure of motilin in isotropic phospholipid bicellar solution. [1]
Identifiers
SymbolMotilin_ghrelin
Pfam PF04644
InterPro IPR006738
SCOP2 1lbj / SCOPe / SUPFAM
OPM superfamily 145
OPM protein 1lbj
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Motilin
Motilin Image.png
NMR solution structure of motilin in phospholipid bicellar solution. [1]
Identifiers
SymbolMLN
NCBI gene 4295
HGNC 7141
OMIM 158270
PDB 1lbj
RefSeq NM_001040109
UniProt P12872
Other data
Locus Chr. 6 p21.3-p21.2
Search for
Structures Swiss-model
Domains InterPro

Motilin is a 22-amino acid polypeptide hormone in the motilin family that, in humans, is encoded by the MLN gene. [2]

Contents

Motilin is secreted by endocrine Mo cells [3] [4] (also referred to as M cells, which are not the same as the M cells, or microfold cells, found in Peyer's patches) that are numerous in crypts of the small intestine, especially in the duodenum and jejunum. [5] 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. [6] 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, the motilin receptor has been identified in the gastrointestinal tracts of pigs, rats, cows, and cats, and in the central nervous system of rabbits.

Discovery

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." [7]

Structure

Motilin has 22 amino acids and molecular weight of 2698 daltons. 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. [8]

The sequences of amino acids of motilin is: Phe-Val-Pro-Ile-Phe-Thr-Tyr-Gly-Glu-Leu-Gln-Arg-Met-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly-Gln. [9]

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. [1]

Stimulus

How the secretion of motilin is regulated is largely unknown, although some studies suggest that an alkaline pH in the duodenum stimulates its release. However, 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. [10] Intravenous injection of glucose, which increases the release of insulin, is also found to inhibit cyclic elevation of plasma motilin. [11] Other studies on dogs have also suggested that motilin acted as endogenous ligand in positive feedback mechanism to stimulate the release of more motilin. [12] In dogs and cats, motilin secretion is stimulated by hydrogen ions (protons) and lipids when the animal is in a "fed" state. However, during fasting, motilin is periodically released into the serum to initiate phase III of the migrating motor complex. [13]

Function

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. [9] 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. [14]

Motilin agonists

Erythromycin, Mitemcinal and related antibiotics act as non-peptide motilin agonists, and are sometimes used for their ability to stimulate gastrointestinal motility. In the case of erythromycin, it is its hemiketal intermediate, formed after an oral dose in the low-pH environment of the stomach lumen, which directly acts on the motilin receptor. [15] 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.

Camicinal is a motilin agonist under development.

Xylitol ingestion also increases motilin secretion, which may be related to xylitol's ability to cause diarrhea. [16]

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. [17] 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.

Human proteins

GHRL; Motilin;

Related Research Articles

<span class="mw-page-title-main">Ghrelin</span> Peptide hormone involved in appetite regulation

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<span class="mw-page-title-main">Vasoactive intestinal peptide</span> Hormone that affects blood pressure / heart rate

Vasoactive intestinal peptide, also known as vasoactive intestinal polypeptide or VIP, is a peptide hormone that is vasoactive in the intestine. VIP is a peptide of 28 amino acid residues that belongs to a glucagon/secretin superfamily, the ligand of class II G protein–coupled receptors. VIP is produced in many tissues of vertebrates including the gut, pancreas, cortex, and suprachiasmatic nuclei of the hypothalamus in the brain. VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gallbladder. In humans, the vasoactive intestinal peptide is encoded by the VIP gene.

<span class="mw-page-title-main">Gastric inhibitory polypeptide</span> Mammalian protein found in Homo sapiens

Gastric inhibitory polypeptide(GIP), also known as glucose-dependent insulinotropic polypeptide, is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor of gastric acid secretion, its main role, being an incretin, is to stimulate insulin secretion.

Growth hormone–releasing hormone (GHRH), also known as somatocrinin among other names in its endogenous form and as somatorelin (INN) in its pharmaceutical form, is a releasing hormone of growth hormone (GH). It is a 44-amino acid peptide hormone produced in the arcuate nucleus of the hypothalamus.

<span class="mw-page-title-main">Obestatin</span> Hormone that is produced in the stomach

Obestatin is a hormone that is produced in specialized epithelial cells of the stomach and small intestine of several animals including humans. Obestatin was originally identified as an anorectic peptide, but its effect on food intake remains controversial.

Xenin is a peptide hormone secreted from the chromogranin A-positive enteroendocrine cells called the K-cells in the mucous membrane of the duodenum and stomach of the upper gut. The peptide has been found in humans, dogs, pigs, rats, and rabbits.

<span class="mw-page-title-main">Pancreatic polypeptide</span> Protein produced by the endocrine pancreas

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<span class="mw-page-title-main">Enteroendocrine cell</span> Cell that produces gastrointestinal hormones

Enteroendocrine cells are specialized cells of the gastrointestinal tract and pancreas with endocrine function. They produce gastrointestinal hormones or peptides in response to various stimuli and release them into the bloodstream for systemic effect, diffuse them as local messengers, or transmit them to the enteric nervous system to activate nervous responses. Enteroendocrine cells of the intestine are the most numerous endocrine cells of the body. They constitute an enteric endocrine system as a subset of the endocrine system just as the enteric nervous system is a subset of the nervous system. In a sense they are known to act as chemoreceptors, initiating digestive actions and detecting harmful substances and initiating protective responses. Enteroendocrine cells are located in the stomach, in the intestine and in the pancreas. Microbiota play key roles in the intestinal immune and metabolic responses in these enteroendocrine cells via their fermentation product, acetate.

<span class="mw-page-title-main">Motilin receptor</span> Protein-coding gene in the species Homo sapiens

Motilin receptor is a G protein-coupled receptor that binds motilin. It was first cloned in 1999 by Merck Laboratories. and scientists have since been searching for compounds to modify its behavior.

<span class="mw-page-title-main">Growth hormone secretagogue receptor</span> Protein-coding gene in the species Homo sapiens

Growth hormone secretagogue receptor(GHS-R), also known as ghrelin receptor, is a G protein-coupled receptor that binds growth hormone secretagogues (GHSs), such as ghrelin, the "hunger hormone". The role of GHS-R is thought to be in regulating energy homeostasis and body weight. In the brain, they are most highly expressed in the hypothalamus, specifically the ventromedial nucleus and arcuate nucleus. GSH-Rs are also expressed in other areas of the brain, including the ventral tegmental area, hippocampus, and substantia nigra. Outside the central nervous system, too, GSH-Rs are also found in the liver, in skeletal muscle, and even in the heart.

<span class="mw-page-title-main">GHRP-6</span> Chemical compound

Growth hormone-releasing peptide 6 (GHRP-6), also known as growth hormone-releasing hexapeptide, is one of several synthetic met-enkephalin analogues that include unnatural D-amino acids, were developed for their growth hormone-releasing activity and are called growth hormone secretagogues. They lack opioid activity but are potent stimulators of growth hormone (GH) release. These secretagogues are distinct from growth hormone releasing hormone (GHRH) in that they share no sequence relation and derive their function through activation of a completely different receptor. This receptor was originally called the growth hormone secretagogue receptor (GHSR), but due to subsequent discoveries, the hormone ghrelin is now considered the receptor's natural endogenous ligand, and it has been renamed as the ghrelin receptor. Therefore, these GHSR agonists act as synthetic ghrelin mimetics.

<span class="mw-page-title-main">Ibutamoren</span> Experimental drug

Ibutamoren is a potent, long-acting, orally-active, selective, and non-peptide agonist of the ghrelin receptor and a growth hormone secretagogue, mimicking the growth hormone (GH)-stimulating action of the endogenous hormone ghrelin. It has been shown to increase the secretion of several hormones including GH and insulin-like growth factor 1 (IGF-1) and produces sustained increases in the plasma levels of these hormones while also raising cortisol levels.

<span class="mw-page-title-main">Tabimorelin</span> Chemical compound

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<span class="mw-page-title-main">Mitemcinal</span> Chemical compound

Mitemcinal is a motilin agonist derived from the macrolide antibiotic, erythromycin. It was discovered in the labs of Chugai Pharma. Mitemcinal is orally administered and it is believed to have strong promotility effects. Promotility drugs relieve symptoms of reflux by speeding the clearance of acid from the oesophagus and stomach. The parent compound, erythromycin, has these characteristics, but mitemcinal lacks the antibiotic properties of erythromycin.

Growth hormone secretagogues or GH secretagogues (GHSs) are a class of drugs which act as secretagogues of growth hormone (GH). They include agonists of the ghrelin/growth hormone secretagogue receptor (GHSR), such as ghrelin (lenomorelin), pralmorelin (GHRP-2), GHRP-6, examorelin (hexarelin), ipamorelin, and ibutamoren (MK-677), and agonists of the growth hormone-releasing hormone receptor (GHRHR), such as growth hormone-releasing hormone, CJC-1295, sermorelin, and tesamorelin.

<span class="mw-page-title-main">Relamorelin</span> Chemical compound

Relamorelin is a synthetic peptide, centrally penetrant, selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) which is under development by Allergan pharmaceuticals for the treatment of diabetic gastroparesis, chronic idiopathic constipation, and anorexia nervosa. It is a pentapeptide and an analogue of ghrelin with improved potency and pharmacokinetics. In humans, relamorelin produces increases in plasma growth hormone, prolactin, and cortisol levels, and, like other GHSR agonists, increases appetite. As of June 2015, relamorelin is in phase II clinical trials for diabetic gastroparesis and constipation. The United States Food and Drug Administration (FDA) has granted Fast Track designation to relamorelin for diabetic gastroparesis. The development of the drug is uncertain as the most recent mention of it was in a 2019 SEC filing from the drug manufacturer lists the drug's expected launch year as 2024, but not in subsequent filings or press releases.

<span class="mw-page-title-main">Ipamorelin</span> Peptide selective agonist of the ghrelin/growth hormone secretagogue receptor

Ipamorelin (INN) (developmental code name NNC 26-0161) is a peptide selective agonist of the ghrelin/growth hormone secretagogue receptor (GHS) and a growth hormone secretagogue. It is a pentapeptide with the amino acid sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2 that was derived from GHRP-1.

<span class="mw-page-title-main">Ulimorelin</span> Chemical compound

Ulimorelin is a drug with a modified cyclic peptide structure which acts as a selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR-1a). Unlike many related drugs, ulimorelin has little or no effect on growth hormone (GH) release in rats. However, like ghrelin and other ghrelin agonists, ulimorelin does stimulate GH release with concomitant increases in insulin-like growth factor 1 (IGF-1) in humans. It has been researched for enhancing gastrointestinal motility, especially in gastroparesis and in aiding recovery of bowel function following gastrointestinal surgery, where opioid analgesic drugs used for post-operative pain relief may worsen existing constipation. While ulimorelin has been shown to increase both upper and lower gastrointestinal motility in rats, and showed promising results initially in humans, it failed in pivotal clinical trials in post operative ileus.

References

  1. 1 2 3 PDB: 1lbj ​; Andersson A, Mäler L (October 2002). "NMR solution structure and dynamics of motilin in isotropic phospholipid bicellar solution". Journal of Biomolecular NMR. 24 (2): 103–12. doi:10.1023/A:1020902915969. PMID   12495026. S2CID   34766985.
  2. ↑ 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.
  3. ↑ Daniel EE (1990-12-11). Neuropeptide Function in the Gastrointestinal Tract. CRC Press. ISBN   9780849361586.
  4. ↑ Goswami C, Shimada Y, Yoshimura M, Mondal A, Oda S, Tanaka T, Sakai T, Sakata I (2015-06-26). "Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in Suncus murinus". PLOS ONE. 10 (6): e0131554. Bibcode:2015PLoSO..1031554G. doi: 10.1371/journal.pone.0131554 . PMC   4482737 . PMID   26115342.
  5. ↑ 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. S2CID   220582156.
  6. ↑ Itoh Z (1997). "Motilin and clinical application". Peptides. 18 (4): 593–608. doi:10.1016/S0196-9781(96)00333-6. PMID   9210180. S2CID   38242445.
  7. ↑ 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.
  8. ↑ DeGroot LJ (1989). McGuigan JE (ed.). Endocrinology . Philadelphia: Saunders. p. 2748. ISBN   978-0-7216-2888-2.
  9. 1 2 Williams RL (1981). Textbook of endocrinology (6th ed.). Philadelphia: Saunders. pp.  704–705. ISBN   978-0-7216-9398-9.
  10. ↑ 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. S2CID   23526142.
  11. ↑ 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.
  12. ↑ 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. doi:10.1016/0016-5085(84)90128-8. PMID   6724277.
  13. ↑ Washabau RJ (2013). "Integration of Gastrointestinal Function". In Robert J. Washabau, Michael J. Day (eds.). Canine and Feline Gastroenterology. Elsevier. pp. 1–31. doi:10.1016/B978-1-4160-3661-6.00001-8. ISBN   9781416036616 . Retrieved 22 January 2023.
  14. ↑ Frohman LA, Felig P (2001). Ghosh PK, O'Dorisio TM (eds.). Endocrinology & metabolism. New York: McGraw-Hill, Medical Pub. Div. p. 1330. ISBN   978-0-07-022001-0.
  15. ↑ Galligan JJ, Vanner S (October 2005). "Basic and clinical pharmacology of new motility promoting agents". Neurogastroenterology and Motility. 17 (5): 643–53. doi: 10.1111/j.1365-2982.2005.00675.x . PMID   16185302. S2CID   7298061.
  16. ↑ Wölnerhanssen BK, Meyer-Gerspach AC, Beglinger C, Islam MS (June 2019). "Metabolic effects of the natural sweeteners xylitol and erythritol: A comprehensive review". Critical Reviews in Food Science and Nutrition. 60 (12): 1986–1998. doi:10.1080/10408398.2019.1623757. PMID   31204494. S2CID   189944738.
  17. ↑ Kojima M, Hosoda H, Matsuo H, Kangawa K (April 2001). "Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor". Trends in Endocrinology and Metabolism. 12 (3): 118–22. doi:10.1016/S1043-2760(00)00362-3. PMID   11306336. S2CID   42054657.
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