Motilin Comparative Study: Structure, Distribution, Receptors, and Gastrointestinal Motility

Abstract

Motilin, produced in endocrine cells in the mucosa of the upper intestine, is an important regulator of gastrointestinal (GI) motility and mediates the phase III of interdigestive migrating motor complex (MMC) in the stomach of humans, dogs and house musk shrews through the specific motilin receptor (MLN-R). Motilin-induced MMC contributes to the maintenance of normal GI functions and transmits a hunger signal from the stomach to the brain. Motilin has been identified in various mammals, but the physiological roles of motilin in regulating GI motility in these mammals are well not understood due to inconsistencies between studies conducted on different species using a range of experimental conditions. Motilin orthologs have been identified in non-mammalian vertebrates, and the sequence of avian motilin is relatively close to that of mammals, but reptile, amphibian and fish motilins show distinctive different sequences. The MLN-R has also been identified in mammals and non-mammalian vertebrates, and can be divided into two main groups: mammal/bird/reptile/amphibian clade and fish clade. Almost 50 years have passed since discovery of motilin, here we reviewed the structure, distribution, receptor and the GI motility regulatory function of motilin in vertebrates from fish to mammals.

Keywords: comparative biology; enteric nerves; gastrointestinal contractility; motilin; motilin receptor; smooth muscle; vagus afferent nerves.

Figure 1

Molecular phylogenetic analysis of motilin receptor in vertebrates. The evolutionary history was inferred by using the Maximum Likelihood method based on the JTT matrix-based model. The tree with the highest log likelihood (-7475.17) is shown. The percentage of trees in which the associated taxa clustered together is shown next to the branches. Initial tree(s) for the heuristic search were obtained automatically by applying Neighbor-Join and BioNJ algorithms to a matrix of pairwise distances estimated using a JTT model, and then selecting the topology with superior log likelihood value. The tree is drawn to scale, with branch lengths measured in the number of substitutions per site. The analysis involved 33 amino acid sequences. All positions containing gaps and missing data were eliminated. There were a total of 264 positions in the final dataset. Evolutionary analyses were conducted in MEGA7.

Figure 2

Comparison of contractile efficacy of different vertebrate motilins in isolated muscle strips from rabbit duodenum, chicken ileum and Japanese fire belly newt stomach. Isolated GI muscle strips from each animal were incubated in an organ bath containing bubbled physiological salt solution. Motilins were applied in the organ bath and evoked muscle contractions were measured by a force-transducer. Using this equipment, GI muscle-contracting actions of human, chicken, alligator, turtle, newt and zebrafish motilins were compared in the isolated rabbit duodenum (A), chicken ileum (B) and Japanese fire belly newt stomach (C). The symbols indicate concentration-response curves for the six motilins (human, chicken, alligator, turtle, newt and zebrafish). The Y axis indicates the relative amplitude of contraction normalized by the response of 10^-4 M acetylcholine. Each symbol indicates the means ± SEM of results of at least five experiments. Homologous motilin showed the strongest response in respective GI strips (rabbit duodenum vs. human motilin; chicken ileum vs. chicken motilin; newt stomach vs. newt motilin).

Figure 3

Potential mechanisms of motilin-induced GI motor-stimulating actions. Motilin is synthesized in the M cells of the upper GI tract and is released by various stimuli, including mechanical, chemical, and biological. The released motilin causes GI motility-stimulating actions through motilin receptors (MLN-Rs) located on enteric neurons and smooth muscle cells. Neural pathways in the enteric nervous system are complex. Motilin stimulates neural pathways including cholinergic nicotinic receptors (black), adrenergic receptors, serotonin (5-HT) receptors and NO neurons, and finally acetylcholine (ACh, blue triangle) released from cholinergic neurons (blue) acts on muscarinic receptors (Mus-R) on smooth muscle cells to cause contraction of stomach and upper intestine. Results of experiments in conscious animals (dogs, humans and Suncus) indicate that motilin stimulates the release of 5-HT from enteric serotonergic neurons (green) and 5-HT (green triangle) activates both enteric cholinergic neurons and the vago-vagal reflex pathway through activation of the 5-HT₃ receptors on enteric neurons and afferent vagal terminals. The stimulation of vagus efferent neurons activates neurons in the myenteric plexus to cause contraction of stomach. Since MLN-R is also present in the intestinal mucosa, it is possible that motilin acts on enterochromaffin cells (EC cells) to release 5-HT. The 5-HT originating from EC cells could also act on enteric neurons and the vagus afferent terminals. The contribution of these mechanisms might be different depending on the species, regions, and experimental conditions. The vago-vagal reflex pathway has been demonstrated mainly in the stomach but not in the small intestine. The MLN-R is also expressed in the CNS, but its functional roles in stimulating GI motility is unknown.