Effects of famotidine on motilin, and co-administration of motilin and ghrelin-stimulated gastric acid secretion.

<p>Gastric acid secretion was stimulated with histamine (1 mg/kg BW) (A, B), motilin (10 μg/kg BW) (D, E) and co-administration of motilin (10 μg/kg BW) and ghrelin (10 μg/kg BW) (G, H) with or without famotidine (0.33 mg/kg BW). In the left and middle panels, vehicle/famotidine was administrated intravenously 30 min before histamine (A, B), motilin (D, E) and co-administration of motilin and ghrelin (G, H). Gastric acid secretion (blue line) and pH (red line) changes were monitored at 10-min intervals throughout the experiment. Right panels represent the net change in cumulative acid output for 50 min after administration of histamine (C), motilin (F) and co-administration of motilin and ghrelin (I) with pre-administration of vehicle or famotidine. Each value represents the mean ± SEM. <i>p</i> < 0.05 was considered statistically significant. F: famotidine; G: ghrelin; M: motilin, figures after the abbreviations denote concentration in μg/kg. n = 3–4.</p

Effects of atropine on motilin, and co-administration of motilin and ghrelin-stimulated gastric acid secretion.

<p>Gastric acid secretion (blue line) and pH (red line) changes were monitored at 10-min intervals throughout the experiment. In the left and middle panels, intravenous administration of either vehicle or atropine (30 μg/kg BW) was done 30 min before carbachol (5 μg/kg BW) (A, B), motilin (10 μg/kg BW) (D, E) and co-administration of motilin and ghrelin (G,H) treatment. Right panels compare the net change in cumulative acid output for 50 min after administration of carbachol (C), motilin (F) and co-administration of motilin and ghrelin (I) with vehicle or atropine pretreatment. Each value represents the mean ± SEM. <i>p</i> < 0.05 was considered statistically significant. A: atropine; C: carbachol; G: ghrelin; M: motilin, figures after the abbreviations denote concentration in μg/kg. n = 3.</p

The effect of ghrelin administration on phase II of the MMC.

<p>Ghrelin (0.1, 0.3, 1, 3, or 10 µg·kg⁻¹·min⁻¹ for 10 min) was intravenously administered during phase II of the MMC (10 min after the initiation of phase II) in sham-operated (A) and vagotomized (B) suncus. Ghrelin administration was found to enhance the phase II contraction in sham-operated suncus but not vagotomized suncus. (C) The motility index was statistically increased in sham-operated suncus compared with vagotomized suncus. * Phase III contractions. #, p<0.05; ##, p<0.01; n = 4.</p

Working hypothesis of the regulatory mechanisms of the MMC and postprandial contractions in suncus.

<p>During the fasted state, endogenous ghrelin secreted from X/A cells acts on the brain and stimulates and maintains gastric phase II of the MMC through vagal efferent nerves. Ghrelin also directly acts on the stomach through the circulation, and initiates gastric phase III contractions in coordination with motilin secreted from M cells (A). Postprandial contractions are initiated and maintained by the vagus nerve, and motilin-induced contractions are inhibited by a vagus nerve–related pathway (B).</p

Spontaneous gastric contractions in sham-operated and vagotomized, fasted suncus.

<p>(A) Regular, cyclic, spontaneous MMC with phase I, II, and III contractions was observed in the stomach of sham-operated suncus. (B) In vagotomized suncus, the amplitude of phase II contractions was decreased, although spontaneous MMC was also observed. Asterisks indicate the phase III contraction. (C) The entire period of the MMC and the duration of phase III were unchanged between sham and vagotomized suncus; however, the duration of phase I was increased in vagotomized suncus. In contrast, the duration of phase II was significantly shorter in vagotomized suncus than in sham-operated animals. (D) The motility index of phase II was significantly lower in vagotomized suncus than in sham-operated suncus. * Phase III contractions. #, p<0.05; ##, p<0.01; n = 5.</p

Effects of motilin and ghrelin on gastric acid secretion.

<p>In urethane-anaesthetized suncus, after a 60-min basal period, gastric acid secretion was measured after administration of histamine (1 mg/kg BW) (A), vehicle (B), ghrelin (0.1, 1.0, and 10 μg/kg BW) (C), motilin (0.1, 1.0, and 10 μg/kg BW) (D), and co-administration of motilin and ghrelin (E). Gastric acid secretion (blue line) and pH (red line) changes were monitored at 10-min intervals throughout the experiment. The net change in cumulative acid output for 50 min after each administration was also calculated (F). Each value represents the mean ± SEM. p < 0.05 was considered statistically significant. G: ghrelin; M: motilin, figures after the abbreviations denote concentration in μg/kg. n = 3–7.</p

Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in <i>Suncus murinus</i>

<div><p>Motilin and ghrelin constitute a peptide family, and these hormones are important for the regulation of gastrointestinal motility. In this study, we examined the effect of motilin and ghrelin on gastric acid secretion in anesthetized suncus (house musk shrew, <i>Suncus murinus</i>), a ghrelin- and motilin-producing mammal. We first established a gastric lumen-perfusion system in the suncus and confirmed that intravenous (i.v.) administration of histamine (1 mg/kg body weight) stimulated acid secretion. Motilin (0.1, 1.0, and 10 μg/kg BW) stimulated the acid output in a dose-dependent manner in suncus, whereas ghrelin (0.1, 1.0, and 10 μg/kg BW) alone did not induce acid output. Furthermore, in comparison with the vehicle administration, the co-administration of low-dose (1 μg/kg BW) motilin and ghrelin significantly stimulated gastric acid secretion, whereas either motilin (1 μg/kg BW) or ghrelin (1 μg/kg BW) alone did not significantly induce gastric acid secretion. This indicates an additive role of ghrelin in motilin-induced gastric acid secretion. We then investigated the pathways of motilin/motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist) had no effect on motilin or motilin-ghrelin co-administration-induced acid output. In contrast, famotidine (a histamine H₂ receptor antagonist) completely inhibited motilin-stimulated acid secretion and co-administration of motilin and ghrelin induced gastric acid output. This is the first report demonstrating that motilin stimulates gastric secretion in mammals. Our results also suggest that motilin and co-administration of motilin and ghrelin stimulate gastric acid secretion via the histamine-mediated pathway in suncus.</p></div

Effects of YM 022 on gastric acid secretion stimulated by motilin, and co-administration of motilin and ghrelin.

<p>Left and middle panels represent the gastric acid secretion (blue line) and pH (red line) changes at 10-min intervals after intravenous administration of vehicle/YM 022 (0.2 mg/kg BW) followed by pentagastrin (1 μg/kg BW) (A, B), motilin (10 μg/kg BW) (D, E) and co-administration of motilin and ghrelin (G,H) throughout the experiment. The net change in cumulative acid output for 50 min after administration of pentagastrin (C), motilin (F) and co-administration of motilin and ghrelin (I) with or without YM 022 pretreatment is shown in the right panels. Each value represents the mean ± SEM. <i>p</i> < 0.05 was considered statistically significant. YM: YM 022; PG: pentagastrin; G: ghrelin; M: motilin, figures after the abbreviations denote concentration in μg/kg. n = 3.</p

Working hypothesis of stimulation of acid secretion by motilin in suncus.

<p>In the duodenum, motilin is secreted by the MO cell during the interdigestive state. It was hypothesized that motilin may directly stimulate histamine release through GPR38 expressed on the ECL cell. Another possibility is the indirect pathway, which is either central or peripheral neural stimulation of motilin for histamine release. Finally, the histamine induced by motilin acts on the parietal cell through the H₂ receptor to release gastric acid. CCKB and muscarinic cholinergic receptors were not found to be involved in motilin-induced gastric acid secretion. MO cell: motilin-producing cell; GPR38: G-protein coupled receptor 38; CCK: cholecystokinin; CCKBR: cholecystokinin B receptor; ECL cell: enterochromaffin-like cell; ACh: Acetylcholine.</p

Study of an RNA-Focused DNA-Encoded Library Informs Design of a Degrader of a r(CUG) Repeat Expansion

A solid-phase DNA-encoded library (DEL) was studied for binding the RNA repeat expansion r(CUG)exp, the causative agent of the most common form of adult-onset muscular dystrophy, myotonic dystrophy type 1 (DM1). A variety of uncharged and novel RNA binders were identified to selectively bind r(CUG)exp by using a two-color flow cytometry screen. The cellular activity of one binder was augmented by attaching it with a module that directly cleaves r(CUG)exp. In DM1 patient-derived muscle cells, the compound specifically bound r(CUG)exp and allele-specifically eliminated r(CUG)exp, improving disease-associated defects. The approaches herein can be used to identify and optimize ligands and bind RNA that can be further augmented for functionality including degradation