Motilin receptor (version 2020.4) in the IUPHAR/BPS Guide to Pharmacology Database

1. University of Cambridge, UK
2. 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. Activation of these receptors by endogenous motilin released from endocrine cells within the mucosa of the duodenum during fasting, induces propulsive phase III movements, part of the gastric migrating motor complex, and promotes the sensation of hunger. 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 gastrointestinal motility; this activity is suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibiotics (often called motilides; e.g. erythromycin), although for many of these molecules the evidence is sparse. Relatively high doses of these compounds may induce vomiting and in humans, nausea.

Contents

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts.

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

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. 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]
6. 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]
7. 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]
8. 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]
9. Depoortere I and Peeters TL. (1995) Transduction mechanism of motilin and motilides in rabbit duodenal smooth muscle. Regul. Pept. 55: 227-35 [PMID:7761622]
10. 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]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. 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]
21. 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
22. 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]
23. 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]
24. 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. -
25. 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]
26. 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]
27. 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]
28. 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]
29. 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]
30. 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]
31. 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]
32. Nieuwenhuijs VB, van Duijvenbode-Beumer H, Verheem A, Visser MR, Verhoef J, Gooszen HG and Akkermans LM. (1999) The effects of ABT-229 and octreotide on interdigestive small bowel motility, bacterial overgrowth and bacterial translocation in rats. Eur. J. Clin. Invest. 29: 33-40 [PMID:10092986]
33. Sanger GJ. (2014) Ghrelin and motilin receptor agonists: time to introduce bias into drug design. Neurogastroenterol. Motil. 26: 149-55 [PMID:24438586]
34. 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]
35. 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]
36. 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]
37. 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]
38. 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]
39. 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]
40. 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]
41. 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]
42. 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]
43. 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]
44. 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]
45. 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]
46. 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]
47. 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]
48. 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]
49. 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]