Motilin

Motilin is a 22-amino acid gastrointestinal hormone secreted by Mo/M cells of the upper small intestine during the fasting state. It is the primary regulator of the migrating motor complex (MMC), the coordinated pattern of gastrointestinal contractions that clear the bowel between meals. Motilin is released in approximately 100-minute cycles during fasting and is a key target for prokinetic drug development for gastroparesis and dysmotility.

Motilin binds the motilin receptor (MLNR), a class A GPCR predominantly expressed on smooth muscle cells and interstitial cells of Cajal in the GI tract. Receptor activation via Gq/11 coupling increases intracellular calcium and triggers coordinated smooth muscle contraction, initiating phase III of the migrating motor complex. Erythromycin and motilide antibiotics function as non-peptide motilin receptor agonists and are used off-label as prokinetics. The motilin-ghrelin receptor system shares structural homology, as both peptides derive from related gene families.

Motilin's role in GI motility has been studied for decades. Clinical interest centers on developing selective motilin receptor agonists for diabetic gastroparesis and chronic intestinal dysmotility. Motilides (erythromycin-derived compounds) show clinical efficacy but are limited by tachyphylaxis. Small-molecule motilin receptor agonists (mitemcinal, camicinal) have advanced to phase II trials for gastroparesis with mixed results. Motilin also coordinates gastric acid secretion and gallbladder emptying during the interdigestive state.