Characterization of the gastric motility response to human motilin and erythromycin in human motilin receptor-expressing transgenic mice

Abstract

Motilin is a gastrointestinal peptide hormone that stimulates gastrointestinal motility. Motilin is produced primarily in the duodenum and jejunum. Motilin receptors (MTLRs) are G proteincoupled receptors that may represent a clinically useful pharmacological target as they can be activated by erythromycin. The functions of motilin are highly species-dependent and remain poorly understood. As a functional motilin system is absent in rodents such as rats and mice, these species are not commonly used for basic studies. In this study, we examine the usefulness of human MTLR-overexpressing transgenic (hMTLR-Tg) mice by identifying the mechanisms of the gastric motor response to human motilin and erythromycin.The distribution of hMTLR was examined immunohistochemically in male wild-type (WT) and hMTLR-Tg mice. The contractile response of gastric strips was measured isometrically in an organ bath, while gastric emptying was determined using phenol red.hMTLR expression was abundant in the gastric smooth muscle layer but more potently expressed in the myenteric plexus of hMTLR-Tg mice but not WT mice. hMTLR was not colocalized with vesicular acetylcholine transporter, a marker of cholinergic neurons in the myenteric plexus. Treatment with human motilin and erythromycin caused concentrationdependent contraction of gastric strips obtained from hMTLR-Tg mice but not from WT mice. 2The contractile response to human motilin and erythromycin in hMTLR-Tg mice was affected by neither atropine nor tetrodotoxin and was totally absent in Ca 2+ -free conditions. Furthermore, intraperitoneal injection of erythromycin significantly promoted gastric emptying in hMTLR-Tg mice but not in WT mice.Human motilin and erythromycin stimulate the gastric motor response in hMTLR-Tg mice. This action is mediated by direct contraction of smooth muscle via the influx of extracellular Ca 2+ . Thus, hMTLR-Tg mice may be useful for the evaluation of MTLR agonists as gastric prokinetic agents.

Enrichment of Motilin Receptor Loss-of-Function Variants in Gastroparesis

“…Recent studies examine the usefulness of human MTLR-overexpressing transgenic mice that could be used for such follow-up experiments (8). Moreover, further studies are warranted to explore whether there are other rare LOF loci, leading to or predisposing to gastroparesis, because currently, these rare variants are explaining only a small proportion of patients with gastroparesis.…”

“…As functional motilin system is absent in rodents, these species are not commonly used for translational studies; hence, the expression of the LOF variants nor lessons from knockout mice are limited. Recent studies examine the usefulness of human MTLR -overexpressing transgenic mice that could be used for such follow-up experiments (8). Moreover, further studies are warranted to explore whether there are other rare LOF loci, leading to or predisposing to gastroparesis, because currently, these rare variants are explaining only a small proportion of patients with gastroparesis.…”