Ghrelin and motilin: two sides of one coin?

Abstract

We would like to emphasize structural and effect-related similarities between the gastrointestinal hormone motilin, the recently discovered agent motilin-related peptide and a novel endogenous ligand of the growth hormone secretagogue receptor (GHS-R), ghrelin. In our opinion, the information summarized below indicates the existence of a family of gastrointestinal hormones linking endocrine control of energy balance and growth with the regulation of gastrointestinal motility. A neuroendocrine system controls gastrointestinal motility at three different levels: the gut itself (enteric nervous system), the autonomic system and higher centers of the central nervous system (1). One way to quantify gastrointestinal motility is to measure the rate of gastric emptying. Gastric emptying depends on several factors: for example in hypoglycemia, rapid gastric emptying is observed (2, 3), whereas physiologic gastroparesis, resulting in impaired absorption of nutrients in the small bowel, has been described in hyperglycemia (4). It is not clear whether the effects of hyperglycemia on gastric motility are the aftermath of direct effects on the smooth muscle since smooth muscle contraction and relaxation are not affected by hyperglycemia in vitro (5). Moreover, foods with a high caloric content are emptied slowly from the stomach as compared with low caloric meals (5). The composition of a meal, (e.g. the proportion of fat, proteins and carbohydrates) is also believed to influence gastric emptying (5). Obviously, a close feed-back control regulation between the above mentioned parameters and the central nervous system exists in healthy individuals and could be disturbed in patients with a neuropathy of the enteric nerve system, (e.g. in patients with long-standing diabetes mellitus (4)). It is still unknown how information about composition and caloric content of a meal is signalled from the stomach to the central nervous system and vice versa. The new hormone ghrelin (6, 7) may participate in this putative regulatory feedback loop between the gastrointestinum and the central structures controlling food intake. Recently Kojima and coworkers identified ghrelin as a ligand of the growth hormone secretagogue receptor (GHS-R) (6), based on its ability to induce GH secretion from pituitary cells. The 28 amino acid peptide hormone is characterized by an octanoyl side chain at serine 3 and its primarily secreted from distinct endocrine cells in the stomach (8). The unique octanoylation feature appears to be essential for the hormone's bioactivity (at least as far as the stimulation of growth hormone secretion is concerned (6)). Prepro-motilin-related peptide (prepro-MTLRP) was first described by Tomasetto and coworkers as a novel hormone originating from enteroendocrine cells of the stomach (9) and shares sequence and structural features with motilin. Despite its motilin like appearance, the authors summarize their findings as follows: `The physiologic contribution of MTLRP to the endocrine regulation of important aspects of GI function such as contraction and/or acid secretion remains to be tested' (9). Although the physiologic roles of motilin, MTLRP and ghrelin are not fully understood, we would like to point out the following facts that may extend the proposed role of this peptide family.