1. University of Cambridge, UK
2. Rakuno Gakuen University, Japan
3. Queen Mary University of London, UK

Abstract

Motilin receptors (provisional nomenclature) are activated by motilin, a 22 amino-acid peptide derived from a precursor (MLN, P12872), which may also generate a motilin-associated peptide. There are significant species differences in the structure of motilin and its receptor, and in the functions of motilin. In humans and large mammals such as dog, activation of these receptors by motilin released from endocrine cells in the duodenal mucosa during fasting, induces propulsive phase III movements. This activity is associated with promoting hunger in humans. In humans and other mammals drugs and other non-peptide compounds which activate the motilin receptor may generate a more long-lasting ability to increase cholinergic activity within the upper gut, to promote upper gastrointestinal motility; this activity is suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibacterials (often called motilides; e.g. erythromycin, azithromycin), although for many of these molecules the evidence is sparse. Relatively high doses may induce vomiting and in humans, nausea.

Contents

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References

1. Asakawa A, Inui A, Momose K, Ueno N, Fujino MA and Kasuga M. (1998) Motilin increases food intake in mice. Peptides 19: 987-90 [PMID:9700745]
2. Barshop K and Kuo B. (2015) The investigational drug camicinal for the treatment of gastroparesis. Expert Opin Investig Drugs 24: 133-140 [PMID:25341626]
3. Boivin MA, Carey MC and Levy H. (2003) Erythromycin accelerates gastric emptying in a dose-response manner in healthy subjects. Pharmacotherapy 23: 5-8 [PMID:12523456]
4. Broad J and Sanger GJ. (2013) The antibiotic azithromycin is a motilin receptor agonist in human stomach: comparison with erythromycin. Br J Pharmacol 168: 1859-67 [PMID:23190027]
5. Buneman P, Christie G, Davies JA, Dimitrellou R, Harding SD, Pawson AJ, Sharman JL and Wu Y. (2020) Why data citation isn't working, and what to do about it Database 2020 [PMID:32367113]
6. Carreras CW, Siani MA, Santi DV and Dillon SB. (2002) Stable expression of a synthetic gene for the human motilin receptor: use in an aequorin-based receptor activation assay. Anal Biochem 300: 146-51 [PMID:11779105]
7. Clark MJ, Wright T, Bertrand PP, Bornstein JC, Jenkinson KM, Verlinden M and Furness JB. (1999) Erythromycin derivatives ABT 229 and GM 611 act on motilin receptors in the rabbit duodenum. Clin Exp Pharmacol Physiol 26: 242-5 [PMID:10081621]
8. Coulie B, Matsuura B, Dong M, Hadac EM, Pinon DI, Feighner SD, Howard AD and Miller LJ. (2001) Identification of peptide ligand-binding domains within the human motilin receptor using photoaffinity labeling. J Biol Chem 276: 35518-22 [PMID:11461914]
9. Dass NB, Hill J, Muir A, Testa T, Wise A and Sanger GJ. (2003) The rabbit motilin receptor: molecular characterisation and pharmacology. Br J Pharmacol 140: 948-54 [PMID:14504130]
10. Depoortere I and Peeters TL. (1995) Transduction mechanism of motilin and motilides in rabbit duodenal smooth muscle. Regul Pept 55: 227-35 [PMID:7761622]
11. Farrugia G, Macielag MJ, Peeters TL, Sarr MG, Galdes A and Szurszewski JH. (1997) Motilin and OHM-11526 activate a calcium current in human and canine jejunal circular smooth muscle. Am J Physiol 273: G404-12 [PMID:9277420]
12. Feighner SD, Tan CP, McKee KK, Palyha OC, Hreniuk DL, Pong SS, Austin CP, Figueroa D, MacNeil D and Cascieri MA et al.. (1999) Receptor for motilin identified in the human gastrointestinal system. Science 284: 2184-8 [PMID:10381885]
13. Feng X, Peeters TL and Tang M. (2007) Motilin activates neurons in the rat amygdala and increases gastric motility. Peptides 28: 625-31 [PMID:17222944]
14. Guan Y, Tang M, Jiang Z and Peeters TL. (2003) Excitatory effects of motilin in the hippocampus on gastric motility in rats. Brain Res 984: 33-41 [PMID:12932837]
15. Haramura M, Okamachi A, Tsuzuki K, Yogo K, Ikuta M, Kozono T, Takanashi H and Murayama E. (2002) Design and synthesis of motilin antagonists derived from the [1-4] fragment of porcine motilin. J Med Chem 45: 670-5 [PMID:11806718]
16. He J, Irwin DM, Chen R and Zhang YP. (2010) Stepwise loss of motilin and its specific receptor genes in rodents. J Mol Endocrinol 44: 37-44 [PMID:19696113]
17. Holst B, Cygankiewicz A, Jensen TH, Ankersen M and Schwartz TW. (2003) High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist. Mol Endocrinol 17: 2201-10 [PMID:12907757]
18. Jadcherla SR and Berseth CL. (2002) Effect of erythromycin on gastroduodenal contractile activity in developing neonates. J Pediatr Gastroenterol Nutr 34: 16-22 [PMID:11753158]
19. Jadcherla SR, Klee G and Berseth CL. (1997) Regulation of migrating motor complexes by motilin and pancreatic polypeptide in human infants. Pediatr Res 42: 365-9 [PMID:9284278]
20. Jia YD, Liu CQ, Tang M and Jiang ZY. (2007) Expression of motilin in the hypothalamus and the effect of central erythromycin on gastric motility in diabetic rats. Neurosci Bull 23: 75-82 [PMID:17592529]
21. Kamerling IM, van Haarst AD, Burggraaf J, Schoemaker RC, de Kam ML, Heinzerling H, Cohen AF and Masclee AA. (2004) Effects of a nonpeptide motilin receptor antagonist on proximal gastric motor function. Br J Clin Pharmacol 57: 393-401 [PMID:15025736]
22. Kitazawa T, Taneike T and Ohga A. (1997) Functional characterization of neural and smooth muscle motilin receptors in the chicken proventriculus and ileum. Regul Pept 71: 87-95 [PMID:9416990]
23. Kitazawa T, Yoshida M, Teraoka H and Kaiya H. (2017) Does motilin peptide regulate gastrointestinal motility of zebrafish? An in vitro study using isolated intestinal strips. Gen Comp Endocrinol 249: 15-23 [PMID:28242309]
24. Koga H, Sato T, Tsuzuki K, Onoda H, Kuboniwa H and Takanashi H. (1994) Potent, acid-stable and orally active macrolide-type motilin receptor agonists, GM-611 and the derivatives. Bioorg Med Chem Lett 4: 1347-1352
25. Li JJ, Chao HG, Wang H, Tino JA, Lawrence RM, Ewing WR, Ma Z, Yan M, Slusarchyk D and Seethala R et al.. (2004) Discovery of a potent and novel motilin agonist. J Med Chem 47: 1704-8 [PMID:15027861]
26. Luiking YC, Peeters TL, Stolk MF, Nieuwenhuijs VB, Portincasa P, Depoortere I, van Berge Henegouwen GP and Akkermans LM. (1998) Motilin induces gall bladder emptying and antral contractions in the fasted state in humans. Gut 42: 830-5 [PMID:9691922]
27. Maguire JJ, Kuc RE and Davenport AP. (2004) Motilin mediates vasoconstriction in human coronary artery in vitro. Proceedings of the British Pharmacological Society, pA₂ online: -
28. Matsuura B, Dong M, Coulie B, Pinon DI and Miller LJ. (2005) Demonstration of a specific site of covalent labeling of the human motilin receptor using a biologically active photolabile motilin analog. J Pharmacol Exp Ther 313: 1101-8 [PMID:15677347]
29. Matsuura B, Dong M and Miller LJ. (2002) Differential determinants for peptide and non-peptidyl ligand binding to the motilin receptor. Critical role of second extracellular loop for peptide binding and action. J Biol Chem 277: 9834-9 [PMID:11781320]
30. Matsuura B, Dong M, Naik S, Miller LJ and Onji M. (2006) Differential contributions of motilin receptor extracellular domains for peptide and non-peptidyl agonist binding and activity. J Biol Chem 281: 12390-6 [PMID:16531413]
31. McKee KK, Tan CP, Palyha OC, Liu J, Feighner SD, Hreniuk DL, Smith RG, Howard AD and Van der Ploeg LH. (1997) Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics 46: 426-34 [PMID:9441746]
32. Miller P, Roy A, St-Pierre S, Dagenais M, Lapointe R and Poitras P. (2000) Motilin receptors in the human antrum. Am J Physiol Gastrointest Liver Physiol 278: G18-23 [PMID:10644557]
33. Mitselos A, Depoortere I and Peeters TL. (2007) Delineation of the motilin domain involved in desensitization and internalization of the motilin receptor by using full and partial antagonists. Biochem Pharmacol 73: 115-24 [PMID:17074305]
34. Momose K, Inui A, Asakawa A, Ueno N, Nakajima M and Kasuga M. (1998) Anxiolytic effect of motilin and reversal with GM-109, a motilin antagonist, in mice. Peptides 19: 1739-42 [PMID:9880080]
35. Rodríguez-Sinovas A, Jiménez M, De Clercq P, Peeters TL and Vergara P. (1997) Rhythmic oscillating complexes in gastrointestinal tract of chickens: a role for motilin. Am J Physiol 272: G916-22 [PMID:9142926]
36. Sanger GJ. (2014) Ghrelin and motilin receptor agonists: time to introduce bias into drug design. Neurogastroenterol Motil 26: 149-55 [PMID:24438586]
37. Sanger GJ, Holbrook JD and Andrews PL. (2011) The translational value of rodent gastrointestinal functions: a cautionary tale. Trends Pharmacol Sci 32: 402-9 [PMID:21531468]
38. Sanger GJ, Wang Y, Hobson A and Broad J. (2013) Motilin: towards a new understanding of the gastrointestinal neuropharmacology and therapeutic use of motilin receptor agonists. Br J Pharmacol 170: 1323-32 [PMID:23189978]
39. Sanger GJ, Westaway SM, Barnes AA, Macpherson DT, Muir AI, Jarvie EM, Bolton VN, Cellek S, Näslund E and Hellström PM et al.. (2009) GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility. Neurogastroenterol Motil 21: 657-64, e30-1 [PMID:19374732]
40. Sengupta S, Modak P, McCauley N and O'Donnell LJ. (2006) Effect of oral clarithromycin on gall-bladder motility in normal subjects and those with gall-stones. Aliment Pharmacol Ther 24: 95-9 [PMID:16803607]
41. Sharma SS, Bhargava N and Mathur SC. (1995) Effect of oral erythromycin on colonic transit in patients with idiopathic constipation. A pilot study. Dig Dis Sci 40: 2446-9 [PMID:7587829]
42. Strunz U, Domschke W, Mitznegg P, Domschke S, Schubert E, Wünsch E, Jaeger E and Demling L. (1975) Analysis of the motor effects of 13-norleucine motilin on the rabbit, guinea pig, rat, and human alimentary tract in vitro. Gastroenterology 68: 1485-91 [PMID:1132629]
43. Sudo H, Yoshida S, Ozaki K, Muramatsu H, Onoma M, Yogo K, Kamei K, Cynshi O, Kuromaru O and Peeters TL et al.. (2008) Oral administration of MA-2029, a novel selective and competitive motilin receptor antagonist, inhibits motilin-induced intestinal contractions and visceral pain in rabbits. Eur J Pharmacol 581: 296-305 [PMID:18164286]
44. Takanashi H, Yogo K, Ozaki K, Ikuta M, Akima M, Koga H and Nabata H. (1995) GM-109: a novel, selective motilin receptor antagonist in the smooth muscle of the rabbit small intestine. J Pharmacol Exp Ther 273: 624-8 [PMID:7752063]
45. Takanashi H, Yogo K, Ozaki K, Koga H, Itoh Z and Omura S. (2007) In vitro pharmacological characterization of mitemcinal (GM-611), the first acid-resistant non-peptide motilin receptor agonist, in smooth muscle of rabbit small intestine. Pharmacology 79: 137-48 [PMID:17183187]
46. Takeshita E, Matsuura B, Dong M, Miller LJ, Matsui H and Onji M. (2006) Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract. J Gastroenterol 41: 223-30 [PMID:16699856]
47. Thielemans L, Depoortere I, Perret J, Robberecht P, Liu Y, Thijs T, Carreras C, Burgeon E and Peeters TL. (2005) Desensitization of the human motilin receptor by motilides. J Pharmacol Exp Ther 313: 1397-405 [PMID:15764739]
48. Thielemans L, Depoortere I, Van Assche G, Bender E and Peeters TL. (2001) Demonstration of a functional motilin receptor in TE671 cells from human cerebellum. Brain Res 895: 119-28 [PMID:11259768]
49. Thielemans L, Depoortere I, Vanden Broeck J and Peeters TL. (2002) The motilin pharmacophore in CHO cells expressing the human motilin receptor. Biochem Biophys Res Commun 293: 1223-7 [PMID:12054506]
50. Toda N, Shida T, Takano R, Katagiri T, Hirouchi M, Abe M, Soma K, Nakagami Y and Yamazaki M. (2022) Discovery of DS-3801b, a non-macrolide GPR38 agonist with N-methylanilide structure. Bioorg Med Chem Lett 59: 128554 [PMID:35051575]
51. Van Assche G, Depoortere I, Thijs T, Missiaen L, Penninckx F, Takanashi H, Geboes K, Janssens J and Peeters TL. (2001) Contractile effects and intracellular Ca2+ signalling induced by motilin and erythromycin in the circular smooth muscle of human colon. Neurogastroenterol Motil 13: 27-35 [PMID:11169123]
52. Westaway SM and Sanger GJ. (2009) The identification of and rationale for drugs which act at the motilin receptor. Prog Med Chem 48: 31-80 [PMID:21544957]
53. Yamamoto I, Kaiya H, Tsutsui C, Sakai T, Tsukada A, Miyazato M and Tanaka M. (2008) Primary structure, tissue distribution, and biological activity of chicken motilin receptor. Gen Comp Endocrinol 156: 509-14 [PMID:18433751]
54. Zhang S, Kaiya H and Kitazawa T. (2023) Motilin is a regulator of gastric contraction in Japanese fire belly newts (Cynops pyrrhogaster), in vitro studies using isolated gastrointestinal strips of newts, rabbits, and chickens. Gen Comp Endocrinol 330: 114140 [PMID:36228737]
55. Zhang S, Teraoka H, Kaiya H and Kitazawa T. (2021) Motilin- and ghrelin-induced contractions in isolated gastrointestinal strips from three species of frogs. Gen Comp Endocrinol 300: 113649 [PMID:33153968]
56. Zhao DM, Xue HH, Chida K, Suda T, Oki Y, Kanai M, Uchida C, Ichiyama A and Nakamura H. (2000) Effect of erythromycin on ATP-induced intracellular calcium response in A549 cells. Am J Physiol Lung Cell Mol Physiol 278: L726-36 [PMID:10749750]