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.

Why is motilin active in some studies with mice, rats, and guinea pigs, but not in others? Implications for functional variability among rodents

“…Motilin is found within the mammalian kingdom, with orthologues identified in birds, reptiles, amphibians, and fishes; the receptor for motilin, a seven‐transmembrane (TM), G‐protein‐coupled structure (first identified in human 10 ), has a matching presence. 11 , 12 , 13 However, examinations of genomic databases, including those assembled by Ensembl, found that among the mammals, the genes in rodents (mouse, rat, kangaroo rat, guinea pig, squirrel, a strain of pika) for the motilin receptor and often for motilin itself, have become pseudogenes (e.g., 80%–90% identity to the human motilin receptor, but with an in‐frame stop‐codon). This indicates that in rodents the functions of motilin have been lost 11 , 12 , 14 , 15 For the mouse and rat, this is thought to have occurred via mutations in the genes encoding the motilin receptor and motilin, and not by a disruptive chromosomal rearrangement that potentially could have removed both genes.…”

“… Is the variation in response to motilin characteristic for functions that are undergoing gene pseudonymization? In different species of rodent, He et al 11 , 18 described the complete loss of functional genes for motilin and its receptor, but in others, a functional motilin gene remained whilst the receptor was non‐functional (the opposite may be true in certain amphibians 13 ). This variation was argued to have been brought about by early pseudonymization of the motilin receptor followed by progressive pseudonymization of the motilin gene during the evolution of the Rodentia order.…”

“…Interestingly, among the amphibians, the reverse may be true. Certain frogs (e.g., the tropical clawed frog may have retained a motilin receptor but lost the presence of motilin; the authors suggest the possibility of a different endogenous agonist acting at the motilin receptor) 13 …”

“…Certain frogs (e.g., the tropical clawed frog may have retained a motilin receptor but lost the presence of motilin; the authors suggest the possibility of a different endogenous agonist acting at the motilin receptor). 13 Among rodents, the evolutionary pressures that led to the elimination of the presence and functions of motilin are unclear.…”

“…Motilin is found within the mammalian kingdom, with orthologues identified in birds, reptiles, amphibians, and fishes; the receptor for motilin, a seven‐transmembrane (TM), G‐protein‐coupled structure (first identified in human 10 ), has a matching presence 11–13 . However, examinations of genomic databases, including those assembled by Ensembl, found that among the mammals, the genes in rodents (mouse, rat, kangaroo rat, guinea pig, squirrel, a strain of pika) for the motilin receptor and often for motilin itself, have become pseudogenes (e.g., 80%–90% identity to the human motilin receptor, but with an in‐frame stop‐codon).…”