Ghrelin is a 28 amino acids peptide hormone produced in the gastric mucosal X/A-like cells. This peptide has a characteristic structure in which serine at position 3 is modified by fatty acid, such as n-octanoyl acid. Ghrelin acts on a G-protein coupled ghrelin receptor, previously called growth hormone secretagogue receptor (GHS-R) and regulates endocrine and exocrine functions, food intake, drinking water, glucose metabolism, energy homeostasis, cardiovascular function and gastrointestinal (GI) function (motility, secretion and mucosa proliferation). The multifunction of ghrelin is due to widespread distribution of ghrelin receptor in the central nervous system and peripheral organs. Ghrelin has been found mainly in the gastric mucosa and its sequence has been identified in the various vertebrates from fish to mammals. In vertebrate ghrelin, N-terminal sequence (1-7) including the fatty acid modification of 3rd serine is well conserved and this sequence is essential for its biological activity. Therefore, ghrelin is thought to be a multifunctional peptide conserved in the evolution process of vertebrates. In this review although ghrelin is a multifunctional peptide, its GI motility stimulating action has been focused because structures of ghrelin and its receptor are similar with those of motilin and motilin receptor, which are involved in the regulation of migrating motor complex (MMC) in the humans, dogs and house musk shrews (suncus). We summarized the effects of ghrelin on GI motility from fish to mammals (in vivo and in vitro studies) to determine universal function of ghrelin for regulation of GI motility. In mammals, ghrelin shows the GI motility stimulating actions through activation of ghrelin receptor on enteric neurons and primary afferent neurons of vagus nerve in rodentia (mice, rats and guinea-pigs). Enhancement of MMC by ghrelin and decrease of MMC by ghrelin receptor antagonist suggest that ghrelin mediates the phase III of the gastric MMC in mice and rats. However, ghrelin inhibits the gastric MMC in dogs by reduction of motilin release, suggesting that ghrelin depresses the motilin function in dogs. Suncus is a unique experimental animal in which both ghrelin and motilin cause gastric contractions, and ghrelin enhances the motilin action and motilin enhances the ghrelin action. Ghrelin cooperates with motilin for regulation of the gastric MMC in the case of suncus. In humans, ghrelin causes phase III-like contraction of MMC in the stomach at high dose but plasma ghrelin concentration is low and stable during MMC, indicating that ghrelin does not regulate the MMC in the human. In non-mammals, although motilin causes the contraction of bird, amphibian and fish GI tract, there are conspicuous species-related difference in the ghrelininduced actions on GI motility, i.e., ghrelin is effective causing contraction of crop and stomach in the chicken, but it is ineffective in the GI tract of quail and pheasant. In amphibians, ghrelin causes contraction of GI tract in the Xenopus but not in the bullfrogs, black spotted pond frogs and Japanese fire belly newts. In fish, ghrelin contracts zebrafish intestine but fails to cause contraction of goldfish and rainbow trout GI tract. Therefore, the physiological roles of ghrelin in the regulation of GI motility is not clear at present except for rodentia (mice and rats) and suncus. Further comparative biological studies for ghrelin using wide animal species might be necessary in future
