Motilin receptors (provisional nomenclature) are activated by motilin (MLN, P12872), a 22 amino-acid peptide derived from a precursor (MLN, P12872), which may also generate a motilin-associated peptide (MLN, P12872). These receptors promote gastrointestinal motility and are 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.

In terms of structure, the motilin receptor has closest homology with the ghrelin receptor. Thus, the human motilin receptor shares 52% overall amino acid identity with the ghrelin receptor and 86% in the transmembrane regions [8,23-24]. However, differences between the N-terminus regions of these receptors means that their cognate peptide ligands do not readily activate each other [4,21]. In laboratory rodents, the gene encoding the motilin percursor appears to be absent, while the receptor appears to be a pseudogene [8,19]. Functions of motilin (MLN, P12872) are not usually detected in rodents, although brain and other responses to motilin and the macrolide alemcinal have been reported and the mechanism of these actions is obscure [15,17]. Notably, in some non-laboratory rodents (e.g. the North American kangaroo rat (Dipodomys) and mouse (Microdipodops) a functional form of motilin may exist but the motilin receptor is non-functional [11]. Marked differences in ligand affinities for the motilin receptor in dogs and humans may be explained by significant differences in receptor structure [20]. Note that for the complex macrolide structures, selectivity of action has often not been rigorously examined and other actions are possible (e.g. P2X inhibition by erythromycin; [26]). Small molecule motilin receptor agonists are now described [11,21,25]. The motilin receptor does not appear to have constitutive activity [9]. Although not proven, the existence of biased agonism at the receptor has been suggested [14,16,18]. A truncated 5-transmembrane structure has been identified but this is without activity when transfected into a host cell [6]. Receptor dimerisation has not been reported.

* Key recommended reading is highlighted with an asterisk

* De Smet B, Mitselos A, Depoortere I. (2009) Motilin and ghrelin as prokinetic drug targets. Pharmacol. Ther., 123 (2): 207-23. [PMID:19427331]

Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57: 279-288. [PMID:15914470]

* Sanger GJ, Furness JB. (2016) Ghrelin and motilin receptors as drug targets for gastrointestinal disorders. Nat Rev Gastroenterol Hepatol, 13 (1): 38-48. [PMID:26392067]

Sanger GJ, Wang Y, Hobson A, Broad J. (2012) Motilin: Toward a new understanding of the gastrointestinal neuropharmacology and therapeutic use of motilin receptor agonists. Br. J. Pharmacol.,  [Epub ahead of print]. [PMID:23189978]

Takeshita E, Matsuura B, Dong M, Miller LJ, Matsui H, Onji M. (2006) Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract. J Gastroenterol, 41: 223-230. [PMID:16699856]

1. Barshop K, Kuo B. (2015) The investigational drug camicinal for the treatment of gastroparesis. Expert Opin Investig Drugs, 24 (1): 133-140. [PMID:25341626]

2. Broad J, Sanger GJ. (2013) The antibiotic azithromycin is a motilin receptor agonist in human stomach: comparison with erythromycin. Br. J. Pharmacol., 168 (8): 1859-67. [PMID:23190027]

3. Coulie B, Matsuura B, Dong M, Hadac EM, Pinon DI, Feighner SD, Howard AD, Miller LJ. (2001) Identification of peptide ligand-binding domains within the human motilin receptor using photoaffinity labeling. J Biol Chem, 276: 35518-35522. [PMID:11461914]

4. Dass NB, Hill J, Muir A, Testa T, Wise A, Sanger GJ. (2003) The rabbit motilin receptor: molecular characterisation and pharmacology. Br. J. Pharmacol., 140 (5): 948-54. [PMID:14504130]

5. Depoortere I, Peeters TL. (1995) Transduction mechanism of motilin and motilides in rabbit duodenal smooth muscle. Regul. Pept., 55 (3): 227-35. [PMID:7761622]

6. Feighner SD, Tan CP, McKee KK, Palyha OC, Hreniuk DL, Pong SS, Austin CP, Figueroa D, MacNeil D, Cascieri MA, Nargund R, Bakshi R, Abramovitz M, Stocco R, Kargman S, O'Neill G, Van der Ploeg LH, Evans J, Patchett AA, Smith RG, Howard AD. (1999) Receptor for motilin identified in the human gastrointestinal system. Science, 284: 2184-2188. [PMID:10381885]

7. Haramura M, Okamachi A, Tsuzuki K, Yogo K, Ikuta M, Kozono T, Takanashi H, Murayama E. (2002) Design and synthesis of motilin antagonists derived from the [1-4] fragment of porcine motilin. J. Med. Chem., 45 (3): 670-5. [PMID:11806718]

8. He J, Irwin DM, Chen R, Zhang YP. (2010) Stepwise loss of motilin and its specific receptor genes in rodents. J. Mol. Endocrinol., 44 (1): 37-44. [PMID:19696113]

9. Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW. (2003) High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist. Mol Endocrinol., 17: 2201-2210. [PMID:12907757]

10. Koga H, Sato T, Tsuzuki K, Onoda H, Kuboniwa H, Takanashi H. (1994) Potent, acid-stable and orally active macrolide-type motilin receptor agonists, GM-611 and the derivatives. Bioorganic and Medicinal Chemistry Letters, 4 (11): 1347-1352.

11. Li JJ, Chao HG, Wang H, Tino JA, Lawrence RM, Ewing WR, Ma Z, Yan M, Slusarchyk D, Seethala R et al.. (2004) Discovery of a potent and novel motilin agonist. J. Med. Chem., 47 (7): 1704-8. [PMID:15027861]

12. Matsuura B, Dong M, Coulie B, Pinon DI, 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: 1101-1108. [PMID:15677347]

13. Matsuura B, Dong M, 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: 9834-9839. [PMID:11781320]

14. Matsuura B, Dong M, Naik S, Miller LJ, Onji M. (2006) Differential contributions of motilin receptor extracellular domains for peptide and non-peptidyl agonist binding and activity. J Biol Chem, 281: 12390-12396. [PMID:16531413]

15. McKee KK, Tan CP, Palyha OC, Liu J, Feighner SD, Hreniuk DL, Smith RG, Howard AD, 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: 426-434. [PMID:9441746]

16. Mitselos A, Depoortere I, 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 (1): 115-24. [PMID:17074305]

17. Nieuwenhuijs VB, van Duijvenbode-Beumer H, Verheem A, Visser MR, Verhoef J, Gooszen HG, 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 (1): 33-40. [PMID:10092986]

18. Sanger GJ. (2014) Ghrelin and motilin receptor agonists: time to introduce bias into drug design. Neurogastroenterol. Motil., 26 (2): 149-55. [PMID:24438586]

19. Sanger GJ, Holbrook JD, Andrews PL. (2011) The translational value of rodent gastrointestinal functions: a cautionary tale. Trends Pharmacol. Sci., 32 (7): 402-9. [PMID:21531468]

20. Sanger GJ, Wang Y, Hobson A, Broad J. (2012) Motilin: Toward a new understanding of the gastrointestinal neuropharmacology and therapeutic use of motilin receptor agonists. Br. J. Pharmacol.,  [Epub ahead of print]. [PMID:23189978]

21. Sanger GJ, Westaway SM, Barnes AA, Macpherson DT, Muir AI, Jarvie EM, Bolton VN, Cellek S, Näslund E, 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 (6): 657-64, e30-1. [PMID:19374732]

22. Sudo H, Yoshida S, Ozaki K, Muramatsu H, Onoma M, Yogo K, Kamei K, Cynshi O, Kuromaru O, 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 (3): 296-305. [PMID:18164286]

23. Takanashi H, Yogo K, Ozaki K, Koga H, Itoh Z, 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 (3): 137-48. [PMID:17183187]

24. Thielemans L, Depoortere I, Perret J, Robberecht P, Liu Y, Thijs T, Carreras C, Burgeon E, Peeters TL. (2005) Desensitization of the human motilin receptor by motilides. J Pharmacol Exp Ther, 313: 1397-1405. [PMID:15764739]

25. Westaway SM, Sanger GJ. (2009) The identification of and rationale for drugs which act at the motilin receptor. Prog Med Chem, 48: 31-80. [PMID:21544957]

26. Zhao DM, Xue HH, Chida K, Suda T, Oki Y, Kanai M, Uchida C, Ichiyama A, Nakamura H. (2000) Effect of erythromycin on ATP-induced intracellular calcium response in A549 cells. Am. J. Physiol. Lung Cell Mol. Physiol., 278 (4): L726-36. [PMID:10749750]

Anthony P. Davenport Experimental Medicine and Immunoptherapeutics University of Cambridge Level 6, Addenbrooke's Centre for Clinical Investigation (ACCI) Box 110, Addenbrooke's Hospital Cambridge, CB2 0QQ UK