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

Abstract

The gastrointestinal (GI) hormone motilin helps control human stomach movements during hunger and promotes hunger. Although widely present among mammals, it is generally accepted that in rodents the genes for motilin and/or its receptor have undergone pseudonymization, so exogenous motilin cannot function. However, several publications describe functions of low concentrations of motilin, usually within the GI tract and CNS of mice, rats, and guinea pigs. These animals were from institute‐held stocks, simply described with stock names (e.g., “Sprague–Dawley”) or were inbred strains. It is speculated that variation in source/type of animal introduces genetic variations to promote motilin‐sensitive pathways. Perhaps, in some populations, motilin receptors exist, or a different functionally‐active receptor has a good affinity for motilin (indicating evolutionary pressures to retain motilin functions). The ghrelin receptor has the closest sequence homology, yet in non‐rodents the receptors have a poor affinity for each other's cognate ligand. In rodents, ghrelin may substitute for certain GI functions of motilin, but no good evidence suggests rodent ghrelin receptors are highly responsive to motilin. It remains unknown if motilin has functional relationships with additional bioactive molecules formed from the ghrelin and motilin genes, or if a 5‐TM motilin receptor has influence in rodents (e.g., to dimerize with GPCRs and create different pharmacological profiles). Is the absence/presence of responses to motilin in rodents’ characteristic for systems undergoing gene pseudonymization? What are the consequences of rodent supplier‐dependent variations in motilin sensitivity (or other ligands for receptors undergoing pseudonymization) on gross physiological functions? These are important questions for understanding animal variation.

Structural basis for motilin and erythromycin recognition by motilin receptor

“…The importance of the R 12M -D182 ECL2 salt bridge is supported by the deleterious potency of motilin on MTLR with D182A mutation (fig. S6D) and is also in agreement with a previous finding that motilin analog [1][2][3][4][5][6][7][8][9][10][11][12] showed a 158-fold increased binding affinity compared with analog [1][2][3][4][5][6][7][8][9][10][11] (4). The remaining aminoacids, including M 13M , Q 14M , and E 17M , interact with C30 NT and M330 7.28 (Fig.…”

“…The human motilin receptor (MTLR) belongs to class A G protein-coupled receptors (GPCRs) and is the native receptor for motilin (4). Motilin is active in most mammals but does not respond in rodents, in which the genes of motilin and its receptor have become pseudogenes (5)(6)(7). Upon stimulation, MTLR predominantly activates the G q/11 protein, induces Ca 2+ fluxes, and regulates human GI motility (3,8).…”

Phlorizin attenuates postoperative gastric ileus in rats

“…Although the effect of phlorizin was blocked by ghrelin receptor antagonist, we did not directly prove that phlorizin prevented reduced ghrelin signaling induced by LPS. In addition to ghrelin, motilin signaling is also known to contribute to acceleration of GE in humans 27 . However, we did not determine the role of motilin in the effect of phlorizin.…”

“…In addition to ghrelin, motilin signaling is also known to contribute to acceleration of GE in humans. 27 However, we did not determine the role of motilin in the effect of phlorizin. In contrast to humans, rodents lose the functions of motilin due to the lack of functional genes for motilin and its receptor.…”

“…In contrast to humans, rodents lose the functions of motilin due to the lack of functional genes for motilin and its receptor. 27 Thus, human physiology of GE might be somewhat different from the rodents one. Before clinical application of phlorizin, further studies are warranted.…”