The Experts below are selected from a list of 1332 Experts worldwide ranked by ideXlab platform

Takafumi Sakai - One of the best experts on this subject based on the ideXlab platform.

  • RESEARCH ARTICLE Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in Suncus murinus
    2016
    Co-Authors: Chayon Goswami, Takafumi Sakai, Toru Tanaka, Yoshiaki Shimada, Makoto Yoshimura, Ichi Oda, Ichiro Sakata
    Abstract:

    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, Suncus muri-nus), a ghrelin- and Motilin-producing mammal. We first established a gastric lumen-perfu-sion 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) stimu-lated 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 signifi-cantly 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 addi-tive role of ghrelin in Motilin-induced gastric acid secretion. We then investigated the path-ways of Motilin/Motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetyl-choline 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 gas-tric 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

  • involvement of transient receptor potential vanilloid receptor 1 trpv1 expressing vagal nerve in the inhibitory effect of gastric acidification on exogenous Motilin induced gastric phase iii contractions in suncus murinus
    Digestive Diseases and Sciences, 2016
    Co-Authors: Makoto Yoshimura, Takamichi Jogahara, Anupom Mondal, Ichiro Sakata, Kayuri Kuroda, Takashi Mikami, Kazuma Ito, Maki Nishida, Kouhei Koyama, Takafumi Sakai
    Abstract:

    Gastric acidification inhibits Motilin-induced gastric phase III contractions. However, the underlying mechanism has not been thoroughly investigated. Here, we studied the inhibitory mechanism by gastric acidification on Motilin-induced contraction in Suncus murinus (S. murinus). We measured interdigestive gastric phase III contractions in conscious, freely moving S. murinus, and examined the inhibitory effect of gastric acidification on Motilin action and the involvement of the vagus nerve and transient receptor potential vanilloid receptor 1 (TRPV1) in the inhibitory mechanism. A bolus injection of Motilin evoked phase III-like contractions during intravenous infusion of saline. Intragastric acidification (pH 1.5–2.5) inhibited Motilin-induced phase III contractions in a pH-dependent manner and significantly decreased the motility index at a pH below 2.0. In contrast, intraduodenal acidification (pH 2.0) failed to inhibit Motilin-induced contractions. Vagotomy significantly alleviated the suppression of Motilin-induced gastric contractions under acidic conditions (pH 2.0), suggesting vagus nerve involvement. Moreover, intragastric acidification (pH 2.0) significantly increased the number of c-Fos-positive cells in the nucleus tractus solitarii. In vagotomized S. murinus, the number of c-Fos-positive cells did not change, even under gastric acidification conditions. TRPV1 mRNA was highly expressed in the muscle and mucosal regions of the antrum and the nodose ganglion, whereas was not detected in the upper small intestine. Capsazepin, a TRPV1 antagonist, completely rescued the inhibitory effect of gastric acidification. Gastric acidification in S. murinus inhibits Motilin-induced contractions, a finding similar to results observed in humans, while TRPV1-expressing vagus nerves play a role in the inhibitory mechanism.

  • ghrelin is an essential factor for Motilin induced gastric contraction in suncus murinus
    Endocrinology, 2015
    Co-Authors: Kayuri Kuroda, Takamichi Jogahara, Anupom Mondal, Ichiro Sakata, Makoto Yoshimura, Huang Hequing, Takashi Mikami, Shota Takemi, Takafumi Sakai
    Abstract:

    Motilin was discovered in the 1970s as the most important hormone for stimulating strong gastric contractions; however, the mechanisms by which Motilin causes gastric contraction are not clearly understood. Here, we determined the coordinated action of Motilin and ghrelin on gastric motility during fasted and postprandial contractions by using house musk shrew (Suncus murinus; order: Insectivora, suncus named as the laboratory strain). Motilin-induced gastric contractions at phases I and II of the migrating motor complex were inhibited by pretreatment with (d-Lys3)-GHRP-6 (6 mg/kg/h), a ghrelin receptor antagonist. Administration of the Motilin receptor antagonist MA-2029 (0.1 mg/kg) and/or (d-Lys3)-GHRP-6 (0.6 mg/kg) at the peak of phase III abolished the spontaneous gastric phase III contractions in vivo. Motilin did not stimulate gastric contractions in the postprandial state. However, in the presence of a low dose of ghrelin, Motilin evoked phase III–like gastric contractions even in the postprandial ...

  • ghrelin is an essential factor for Motilin induced gastric contraction in suncus murinus
    Endocrinology, 2015
    Co-Authors: Kayuri Kuroda, Takamichi Jogahara, Anupom Mondal, Ichiro Sakata, Makoto Yoshimura, Huang Hequing, Takashi Mikami, Shota Takemi, Kazuma Ito, Takafumi Sakai
    Abstract:

    Motilin was discovered in the 1970s as the most important hormone for stimulating strong gastric contractions; however, the mechanisms by which Motilin causes gastric contraction are not clearly understood. Here, we determined the coordinated action of Motilin and ghrelin on gastric motility during fasted and postprandial contractions by using house musk shrew (Suncus murinus; order: Insectivora, suncus named as the laboratory strain). Motilin-induced gastric contractions at phases I and II of the migrating motor complex were inhibited by pretreatment with (D-Lys(3))-GHRP-6 (6 mg/kg/h), a ghrelin receptor antagonist. Administration of the Motilin receptor antagonist MA-2029 (0.1 mg/kg) and/or (D-Lys(3))-GHRP-6 (0.6 mg/kg) at the peak of phase III abolished the spontaneous gastric phase III contractions in vivo. Motilin did not stimulate gastric contractions in the postprandial state. However, in the presence of a low dose of ghrelin, Motilin evoked phase III-like gastric contractions even in the postprandial state, and postprandial gastric emptying was accelerated. In addition, pretreatment with (D-Lys(3))-GHRP-6 blocked the Motilin-induced gastric contraction in vitro and in vivo, and a γ-aminobutyric acid (GABA) antagonist reversed this block in gastric contraction. These results indicate that blockade of the GABAergic pathway by ghrelin is essential for Motilin-induced gastric contraction.

  • Motilin stimulates pepsinogen secretion in suncus murinus
    Biochemical and Biophysical Research Communications, 2015
    Co-Authors: Chayon Goswami, Takamichi Jogahara, Takafumi Sakai, Toru Tanaka, Ichiro Sakata
    Abstract:

    Abstract Motilin and ghrelin are gastrointestinal hormones that stimulate the migrating motor complex (MMC) of gastrointestinal motility during the fasting state. In this study, we examined the effect of Motilin and ghrelin on pepsinogen secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and Motilin-producing mammal. By using a gastric lumen-perfusion system, we found that the intravenous administration of carbachol and Motilin stimulated pepsinogen secretion, the latter in a dose-dependent manner, whereas ghrelin had no effect. We then investigated the pathways of Motilin-induced pepsinogen secretion using acetylcholine receptor antagonists. Treatment with atropine, a muscarinic acetylcholine receptor antagonist, completely inhibited both carbachol and Motilin-induced pepsinogen secretion. Motilin-induced pepsinogen secretion was observed in the vagotomized suncus. This is the first report demonstrating that Motilin stimulates pepsinogen secretion, and suggest that this effect occurs through a cholinergic pathway in suncus.

Ichiro Sakata - One of the best experts on this subject based on the ideXlab platform.

  • RESEARCH ARTICLE Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in Suncus murinus
    2016
    Co-Authors: Chayon Goswami, Takafumi Sakai, Toru Tanaka, Yoshiaki Shimada, Makoto Yoshimura, Ichi Oda, Ichiro Sakata
    Abstract:

    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, Suncus muri-nus), a ghrelin- and Motilin-producing mammal. We first established a gastric lumen-perfu-sion 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) stimu-lated 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 signifi-cantly 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 addi-tive role of ghrelin in Motilin-induced gastric acid secretion. We then investigated the path-ways of Motilin/Motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetyl-choline 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 gas-tric 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

  • involvement of transient receptor potential vanilloid receptor 1 trpv1 expressing vagal nerve in the inhibitory effect of gastric acidification on exogenous Motilin induced gastric phase iii contractions in suncus murinus
    Digestive Diseases and Sciences, 2016
    Co-Authors: Makoto Yoshimura, Takamichi Jogahara, Anupom Mondal, Ichiro Sakata, Kayuri Kuroda, Takashi Mikami, Kazuma Ito, Maki Nishida, Kouhei Koyama, Takafumi Sakai
    Abstract:

    Gastric acidification inhibits Motilin-induced gastric phase III contractions. However, the underlying mechanism has not been thoroughly investigated. Here, we studied the inhibitory mechanism by gastric acidification on Motilin-induced contraction in Suncus murinus (S. murinus). We measured interdigestive gastric phase III contractions in conscious, freely moving S. murinus, and examined the inhibitory effect of gastric acidification on Motilin action and the involvement of the vagus nerve and transient receptor potential vanilloid receptor 1 (TRPV1) in the inhibitory mechanism. A bolus injection of Motilin evoked phase III-like contractions during intravenous infusion of saline. Intragastric acidification (pH 1.5–2.5) inhibited Motilin-induced phase III contractions in a pH-dependent manner and significantly decreased the motility index at a pH below 2.0. In contrast, intraduodenal acidification (pH 2.0) failed to inhibit Motilin-induced contractions. Vagotomy significantly alleviated the suppression of Motilin-induced gastric contractions under acidic conditions (pH 2.0), suggesting vagus nerve involvement. Moreover, intragastric acidification (pH 2.0) significantly increased the number of c-Fos-positive cells in the nucleus tractus solitarii. In vagotomized S. murinus, the number of c-Fos-positive cells did not change, even under gastric acidification conditions. TRPV1 mRNA was highly expressed in the muscle and mucosal regions of the antrum and the nodose ganglion, whereas was not detected in the upper small intestine. Capsazepin, a TRPV1 antagonist, completely rescued the inhibitory effect of gastric acidification. Gastric acidification in S. murinus inhibits Motilin-induced contractions, a finding similar to results observed in humans, while TRPV1-expressing vagus nerves play a role in the inhibitory mechanism.

  • ghrelin is an essential factor for Motilin induced gastric contraction in suncus murinus
    Endocrinology, 2015
    Co-Authors: Kayuri Kuroda, Takamichi Jogahara, Anupom Mondal, Ichiro Sakata, Makoto Yoshimura, Huang Hequing, Takashi Mikami, Shota Takemi, Takafumi Sakai
    Abstract:

    Motilin was discovered in the 1970s as the most important hormone for stimulating strong gastric contractions; however, the mechanisms by which Motilin causes gastric contraction are not clearly understood. Here, we determined the coordinated action of Motilin and ghrelin on gastric motility during fasted and postprandial contractions by using house musk shrew (Suncus murinus; order: Insectivora, suncus named as the laboratory strain). Motilin-induced gastric contractions at phases I and II of the migrating motor complex were inhibited by pretreatment with (d-Lys3)-GHRP-6 (6 mg/kg/h), a ghrelin receptor antagonist. Administration of the Motilin receptor antagonist MA-2029 (0.1 mg/kg) and/or (d-Lys3)-GHRP-6 (0.6 mg/kg) at the peak of phase III abolished the spontaneous gastric phase III contractions in vivo. Motilin did not stimulate gastric contractions in the postprandial state. However, in the presence of a low dose of ghrelin, Motilin evoked phase III–like gastric contractions even in the postprandial ...

  • ghrelin is an essential factor for Motilin induced gastric contraction in suncus murinus
    Endocrinology, 2015
    Co-Authors: Kayuri Kuroda, Takamichi Jogahara, Anupom Mondal, Ichiro Sakata, Makoto Yoshimura, Huang Hequing, Takashi Mikami, Shota Takemi, Kazuma Ito, Takafumi Sakai
    Abstract:

    Motilin was discovered in the 1970s as the most important hormone for stimulating strong gastric contractions; however, the mechanisms by which Motilin causes gastric contraction are not clearly understood. Here, we determined the coordinated action of Motilin and ghrelin on gastric motility during fasted and postprandial contractions by using house musk shrew (Suncus murinus; order: Insectivora, suncus named as the laboratory strain). Motilin-induced gastric contractions at phases I and II of the migrating motor complex were inhibited by pretreatment with (D-Lys(3))-GHRP-6 (6 mg/kg/h), a ghrelin receptor antagonist. Administration of the Motilin receptor antagonist MA-2029 (0.1 mg/kg) and/or (D-Lys(3))-GHRP-6 (0.6 mg/kg) at the peak of phase III abolished the spontaneous gastric phase III contractions in vivo. Motilin did not stimulate gastric contractions in the postprandial state. However, in the presence of a low dose of ghrelin, Motilin evoked phase III-like gastric contractions even in the postprandial state, and postprandial gastric emptying was accelerated. In addition, pretreatment with (D-Lys(3))-GHRP-6 blocked the Motilin-induced gastric contraction in vitro and in vivo, and a γ-aminobutyric acid (GABA) antagonist reversed this block in gastric contraction. These results indicate that blockade of the GABAergic pathway by ghrelin is essential for Motilin-induced gastric contraction.

  • Motilin stimulates pepsinogen secretion in suncus murinus
    Biochemical and Biophysical Research Communications, 2015
    Co-Authors: Chayon Goswami, Takamichi Jogahara, Takafumi Sakai, Toru Tanaka, Ichiro Sakata
    Abstract:

    Abstract Motilin and ghrelin are gastrointestinal hormones that stimulate the migrating motor complex (MMC) of gastrointestinal motility during the fasting state. In this study, we examined the effect of Motilin and ghrelin on pepsinogen secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and Motilin-producing mammal. By using a gastric lumen-perfusion system, we found that the intravenous administration of carbachol and Motilin stimulated pepsinogen secretion, the latter in a dose-dependent manner, whereas ghrelin had no effect. We then investigated the pathways of Motilin-induced pepsinogen secretion using acetylcholine receptor antagonists. Treatment with atropine, a muscarinic acetylcholine receptor antagonist, completely inhibited both carbachol and Motilin-induced pepsinogen secretion. Motilin-induced pepsinogen secretion was observed in the vagotomized suncus. This is the first report demonstrating that Motilin stimulates pepsinogen secretion, and suggest that this effect occurs through a cholinergic pathway in suncus.

Inge Depoortere - One of the best experts on this subject based on the ideXlab platform.

  • Motilin from gastric motility stimulation to hunger signalling
    Nature Reviews Endocrinology, 2019
    Co-Authors: Eveline Deloose, Inge Depoortere, Wout Verbeure, Jan Tack
    Abstract:

    After the discovery of Motilin in 1972, Motilin and the Motilin receptor were studied intensely for their role in the control of gastrointestinal motility and as targets for treating hypomotility disorders. The genetic revolution - with the use of knockout models - sparked novel insights into the role of multiple peptides but contributed to a decline in interest in Motilin, as this peptide and its receptor exist only as pseudogenes in rodents. The past 5 years have seen a major surge in interest in Motilin, as a series of studies have shown its relevance in the control of hunger and regulation of food intake in humans in both health and disease. Luminal stimuli, such as bitter tastants, have been identified as modulators of Motilin release, with effects on hunger and food intake. The current state of knowledge and potential implications for therapy are summarized in this Review.

  • higher plasma Motilin levels in obese patients decrease after roux en y gastric bypass surgery and regulate hunger
    Gut, 2016
    Co-Authors: Eveline Deloose, Inge Depoortere, Pieter Janssen, Matthias Lannoo, B Van Der Schueren, Jan Tack
    Abstract:

    Objective Motilin-induced phase III contractions of the migrating motor complex (MMC) signal hunger in healthy volunteers. The current aim was to study the role of Motilin as a hunger-inducing factor in obese patients and to evaluate the effect of Roux-en-Y gastric bypass (RYGB) surgery on plasma Motilin levels and hunger scores. Design Motilin and ghrelin plasma levels were determined during a complete MMC cycle in controls and obese patients selected for RYGB before, 6 months and 1 year after surgery. 20 min after the end of the second phase III, obese patients received an intravenous infusion of 40 mg erythromycin. Hunger was scored every 5 min. Hedonic hunger was assessed in obese patients with the Power of Food Scale questionnaire. Results Obesity caused a switch in the origin of phase III from antrum to duodenum. Obese patients had significantly higher Motilin levels compared with controls during the MMC but tended to lack the Motilin peak prior to phase III necessary to trigger hunger. Hunger scores during phase III were significantly lower in obese patients, but could be restored to control levels through the administration of a low dose of the Motilin agonist, erythromycin. After RYGB surgery Motilin, but not ghrelin, levels decreased in parallel with hedonic hunger scores. Conclusions Motilin may be an important regulator involved in the pathogenesis of obesity.

  • endogenous Motilin but not ghrelin plasma levels fluctuate in accordance with gastric phase iii activity of the migrating motor complex in man
    Neurogastroenterology and Motility, 2015
    Co-Authors: Eveline Deloose, Inge Depoortere, Robin Vos, Maura Corsetti, Jan Tack
    Abstract:

    Background Fluctuations in Motilin plasma levels have been implicated in the control of the migrating motor complex (MMC). A plasma peak of Motilin is present before a gastric phase III. Furthermore, not only exogenous administration of Motilin but also ghrelin induces a gastric phase III in man. Aim of this study was to investigate the role of endogenous ghrelin in the regulation of the MMC. Methods Plasma samples for Motilin and ghrelin were taken in between two consecutive phases III of either origin measured using high-resolution manometry. Key Results The duration of 1 complete MMC cycle was on average 95 ± 12 min. Sixty percent of the first phases III and 40% of the second phases III had a gastric origin (p = 0.0574). Motilin (p < 0.05) plasma levels differed significantly between the phases of the MMC but total and octanoylated ghrelin did not. The percentage change in Motilin during the MMC was dependent on the origin of phase III (p < 0.05). Motilin levels increased on average with 35 ± 10% right before a gastric phase III and with 3 ± 4% before a duodenal phase III (p < 0.05). The percentage change in total and octanoylated ghrelin plasma levels was not affected by the origin of phase III. Conclusions & Inferences These results confirm the role of Motilin but not of ghrelin as an endogenous physiological regulator of the MMC with a gastric phase III.

  • Motilin and ghrelin as prokinetic drug targets
    Pharmacology & Therapeutics, 2009
    Co-Authors: Betty De Smet, Anna Mitselos, Inge Depoortere
    Abstract:

    Motilin is a hormone released by the endocrine cells of the duodenal mucosa during fasting to stimulate gastrointestinal motility. Ghrelin, the closest family member of Motilin, was discovered 10 years ago from the rat stomach as the long-awaited endogenous ligand of the growth hormone secretagogue receptor. Ghrelin has now emerged as a multifunctional hormone with important effects on energy homeostasis but also on gastrointestinal motility. Like Motilin, it induces hunger contractions in the fasting state and acts postprandially to accelerate gastric emptying. While the development of Motilin agonists for the treatment of hypomotility disorders has been going on for more than 15 years, the development of ghrelin agonists is still in its infancy. The failure of the first generation of Motilin agonists in clinical trials has been largely due to problems of desensitization and worsening of symptoms due to effects on gastric accommodation. These issues are being taken care of with the second generation of Motilin agonists that are currently under evaluation. Ghrelin agonists have the same potential as Motilin agonists to treat hypomotility disorders but their effects on appetite may even be a bonus to treat disorders such as functional dyspepsia while ghrelin's anti-inflammatory effects may make it superior to Motilin to treat post-operative ileus. Nevertheless the important endocrine activities of ghrelin may result in side effects which are not encountered with Motilin. Future studies will need to point out whether the Motilin-ghrelin receptor family will make it as a new class of gastroprokinetics.

  • synthesis and characterization of site specific biotinylated probes for the Motilin receptor
    International Journal of Peptide and Protein Research, 2009
    Co-Authors: Mark J Macielag, Theo L. Peeters, Inge Depoortere
    Abstract:

    The solid-phase synthesis of two porcine Motilin derivatives, specifically biotinylated on the side chain of Lys20, was accomplished by preactivation of the protected amino acids N alpha-(9-fluorenylmethoxycarbonyl)-N epsilon-biotinyl-L-lysine and N alpha-(9-fluorenylmethoxycarbonyl)-N epsilon-[N-(biotinyl)-6-aminohexanoyl]-L-lysine with BOP/HOBt/DIEA (1:1:2.5) followed by coupling to the support-bound peptide substrate. The biotin moiety was stable to TFA cleavage and repetitive cycles of acylation, as evidenced by the high level of purity (> 80%) of the crude peptides. This direct synthetic approach complements existing orthogonal protection strategies for the site-specific biotinylation of peptides. The derivatized peptides were purified by RP-HPLC and characterized by mass spectral and amino acid analysis. In binding studies using a rabbit antral smooth muscle homogenate, both [Leu13, Lys20 (N epsilon-biotinyl)]porcine Motilin (3) and [Leu13, Lys20 (N epsilon-[N-(biotinyl)-6-aminohexanoyl])]porcine Motilin (4) possessed nearly equal affinities for the Motilin receptor (IC50 = 0.89 and 1.2 nM, respectively) as native porcine Motilin (1) (IC50 = 0.76 nM). The biotinylated peptides were also highly potent in tissue bath assays employing rabbit duodenal smooth muscle segments. In contrast, commercially available [N alpha-biotinylPhe1]porcine Motilin (5) had markedly lower affinity in the binding assay (IC50 = 30 nM). The relative bioactivities of these receptor probes are in accord with previous synthetic studies on Motilin which demonstrated the importance of the amino-terminal segment in the high affinity interaction between the peptide and its receptor. Analog 3 retained high affinity for the Motilin receptor in the presence of avidin. Therefore, this peptide is expected to be a valuable tool for the isolation and identification of Motilin receptors.

Theo L. Peeters - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and characterization of site specific biotinylated probes for the Motilin receptor
    International Journal of Peptide and Protein Research, 2009
    Co-Authors: Mark J Macielag, Theo L. Peeters, Inge Depoortere
    Abstract:

    The solid-phase synthesis of two porcine Motilin derivatives, specifically biotinylated on the side chain of Lys20, was accomplished by preactivation of the protected amino acids N alpha-(9-fluorenylmethoxycarbonyl)-N epsilon-biotinyl-L-lysine and N alpha-(9-fluorenylmethoxycarbonyl)-N epsilon-[N-(biotinyl)-6-aminohexanoyl]-L-lysine with BOP/HOBt/DIEA (1:1:2.5) followed by coupling to the support-bound peptide substrate. The biotin moiety was stable to TFA cleavage and repetitive cycles of acylation, as evidenced by the high level of purity (> 80%) of the crude peptides. This direct synthetic approach complements existing orthogonal protection strategies for the site-specific biotinylation of peptides. The derivatized peptides were purified by RP-HPLC and characterized by mass spectral and amino acid analysis. In binding studies using a rabbit antral smooth muscle homogenate, both [Leu13, Lys20 (N epsilon-biotinyl)]porcine Motilin (3) and [Leu13, Lys20 (N epsilon-[N-(biotinyl)-6-aminohexanoyl])]porcine Motilin (4) possessed nearly equal affinities for the Motilin receptor (IC50 = 0.89 and 1.2 nM, respectively) as native porcine Motilin (1) (IC50 = 0.76 nM). The biotinylated peptides were also highly potent in tissue bath assays employing rabbit duodenal smooth muscle segments. In contrast, commercially available [N alpha-biotinylPhe1]porcine Motilin (5) had markedly lower affinity in the binding assay (IC50 = 30 nM). The relative bioactivities of these receptor probes are in accord with previous synthetic studies on Motilin which demonstrated the importance of the amino-terminal segment in the high affinity interaction between the peptide and its receptor. Analog 3 retained high affinity for the Motilin receptor in the presence of avidin. Therefore, this peptide is expected to be a valuable tool for the isolation and identification of Motilin receptors.

  • effect of Motilin on the discharge of rat hippocampal neurons responding to gastric distension and its potential mechanism
    Peptides, 2008
    Co-Authors: X. Sun, Inge Depoortere, Feifei Guo, Theo L. Peeters
    Abstract:

    The study aims to find the effect of Motilin on neuronal activity of gastric distension-responsive neurons in rat hippocampus and its possible mechanism. Single unit discharges in the hippocampal CA1 region were recorded extracellularly by means of four-barrel glass micropipettes in anesthetized rats and the expression of nNOS in hippocampus was observed by fluo-immunohistochemistry staining. Of the 171 recorded neurons, 76.0% were GD-excitatory (GD-E) neurons and 24.0% were GD-inhibited (GD-I) neurons. The 57.6% of GD-E neurons showed an excitatory response to Motilin and the same effect was observed in 51.7% GD-I neurons. However, when NOS inhibitor nitro-l-arginine methyl ester (l-NAME) was administrated previously, the followed Motilin-induced excitatory responsiveness of GD-responsive neurons was reduced. In contrast, discharge activity of GD-responsive neurons with Motilin was enhanced by pretreatment of NO precursor l-arginine. The expression of nNOS-IR positive neurons was significantly increased in CA1 after administration of Motilin. Our findings suggested that Motilin excited the GD-responsive neurons in the hippocampal CA1 region and the excitatory effect of Motilin may be mediated by the endogenous NO.

  • oral administration of ma 2029 a novel selective and competitive Motilin receptor antagonist inhibits Motilin induced intestinal contractions and visceral pain in rabbits
    European Journal of Pharmacology, 2008
    Co-Authors: Hirokazu Sudo, Kenji Yogo, Kenichi Ozaki, Hiroyasu Muramatsu, Kenshi Kamei, Shoshin Yoshida, Mitsu Onoma, Osamu Cynshi, Osamu Kuromaru, Theo L. Peeters
    Abstract:

    Abstract The pharmacological properties of MA-2029, a novel Motilin receptor antagonist, were investigated. In vitro , MA-2029 (1 to 30 nM) competitively inhibited Motilin-induced contractions in isolated rabbit duodenal longitudinal muscle strips, with a pA 2 value of 9.17 ± 0.01 ( n  = 5). However, contractile responses to acetylcholine and substance P were unaffected even at 1 μM of MA-2029. MA-2029 concentration-dependently inhibited the binding of [ 125 I]Motilin to Motilin receptors in a homogenate of rabbit colon smooth muscle tissue and membranes of HEK 293 cells expressing human Motilin receptors. The p K i of MA-2029 was 8.58 ± 0.04 in the rabbit colon homogenate ( n  = 4) and 8.39 in the HEK 293 cells (mean of duplicate experiments). In vivo , orally-administered MA-2029 (3 to 30 mg/kg) dose-dependently inhibited colonic contractions induced by Motilin (3 μg/kg, i.v.) in conscious rabbits. Inhibition was caused by all doses at 30 min after administration and by 10 mg/kg or more at 4 h after administration. The plasma concentration of MA-2029 correlated with its inhibitory effect. Furthermore, the oral administration of MA-2029 (0.3 to 3 mg/kg) also inhibited abdominal muscle contractions (an index of the visceral pain) induced by intravenous infusion of Motilin (3 μg/kg/h) during colorectal distension in conscious rabbits. These results indicate that MA-2029 is an orally active, selective and competitive Motilin receptor antagonist. It is suggested that this compound may be useful for gastrointestinal disorders associated with disturbed gastrointestinal motility such as irritable bowel syndrome.

  • Motilin activates neurons in the rat amygdala and increases gastric motility
    Peptides, 2007
    Co-Authors: Xin Feng, Theo L. Peeters, Ming Tang
    Abstract:

    Motilin and Motilin receptors have been found in most regions of the brain, including the amygdala, one of the most important parts of the limbic system. Our previous study found that administration of Motilin in the hippocampus stimulates gastric motility. We now explore the effect of Motilin in the amygdala on gastric motility. In conscious rats, gastric motility was recorded after microinjection of Motilin, Motilin receptor antagonist (GM-109) or a mixture of the two into the basomedial amygdala nucleus (BMA). In anesthetized rats the changes of spontaneous discharges of gastric distention sensitive neurons (GDSN) in the BMA were recorded after intracerebroventricular (i.c.v.) microinjection of Motilin or GM-109. In conscious rats the amplitude of gastric contractions increased dose-dependently after microinjection of Motilin in the BMA, and decreased after microinjection of GM-109. The excitatory or inhibitory effects induced by Motilin or GM-109 alone, were weakened by microinjection of a mixture solution of both. The spontaneous discharge frequency of gastric distention excitatory neuron (GDEN) was mainly inhibited by i.c.v. microinjection of Motilin but excited by GM-109. In contrast, the spontaneous discharge frequency of gastric distention inhibitory neuron (GDIN) was mainly excited by Motilin, but inhibited by GM-109. Our findings suggest that Motilin may regulate gastric motility by modulating neural pathways in the BMA.

  • Motilin and erythromycin a share a common binding site in the third transmembrane segment of the Motilin receptor
    Biochemical Pharmacology, 2005
    Co-Authors: Inge Depoortere, Patrick Robberecht, Pascale Vertongen, Magali Waelbroeck, Theo L. Peeters
    Abstract:

    Abstract The Motilin receptor (MTLR) represents a clinically useful pharmacological target, as agonists binding to the MTLR have gastroprokinetic properties. In order to compare the molecular basis for interaction of the MTLR with Motilin and with the non-peptide Motilin agonist, erythromycin-A (EM-A), the negatively charged E 119 located in the third transmembrane (TM 3 ) region was mutated to D (E119D) and Q (E119Q), respectively, and changes in activity of the mutant receptors were verified. Methods: Each mutant receptor was stably transfected in CHO-cells containing the Ca 2+ indicator apo-aequorin. Receptor activation in response to Motilin, EM-A and their analogues was assessed by Ca 2+ -luminescense. Results: In the E119Q mutant, the Ca 2+ response to Motilin and EM-A was abolished while in the E119D mutant it was reduced with 62% (Motilin) and 81% (EM-A). The pEC 50 values were shifted from 9.65 ± 0.03 to 7.41 ± 0.09 (Motilin) and from 6.63 ± 0.12 to 4.60 ± 0.07 (EM-A). Acetylation of the N-terminal amine group as in [ N -acetyl-Phe] 1 mot (1–14), decreased the potency 6.3-fold (WT-MTLR) and 148-fold (E119D). Acetylation of EM-A enol ether induced a more pronounced shift in potency: 7943-fold (WT-MTLR) and 1413-fold (E119D). Conclusion: The comparable loss of affinity of the mutant receptors for Motilin and EM-A indicate that these agonists both interact with the TM 3 domain of the MTLR. The results with acetylated derivatives support an ionic interaction between E 119 of the MTLR with the N + of the desosamine sugar in EM-A, but not with the N + of the free amine group in Motilin.

T L Peeters - One of the best experts on this subject based on the ideXlab platform.

  • differential effects of Motilin on interdigestive motility of the human gastric antrum pylorus small intestine and gallbladder
    Neurogastroenterology and Motility, 2003
    Co-Authors: Y C Luiking, T L Peeters, L M A Akkermans, A C Van Der Reijden, G P Van Bergehenegouwen
    Abstract:

    Differential effects of Motilin on interdigestive motility of the human gastric antrum, pylorus, small intestine and gallbladder. Luiking YC, Akkermans LM, van der Reijden AC, Peeters TL, van Berge-Henegouwen GP. Gastrointestinal Research Unit, Department of Surgery, University Medical Centre Utrecht, The Netherlands. yc.luiking@ah.unimaas.nl Motilin was infused in this study with the aim of examining refractory characteristics for Motilin stimulation of antral phase III and fasting gallbladder emptying. Moreover, interdigestive pyloric and small intestinal motility from duodenum to ileum were studied, as these may be target organs for Motilin. Eight fasting, healthy male volunteers received, on separate subsequent days, repeated infusions of 13leucine-Motilin (8 pmol (kg min)(-1) for 5 min) or saline at 30 min after phase IIIs in the duodenum. Interdigestive motility of the antrum, pylorus, duodenum, jejunum and ileum was measured for maximum 10 h by using a 21-lumen perfused catheter. Gallbladder motility was measured by ultrasonography. Motilin infusions induced antral phase IIIs, but only after a preceding phase III of duodenal origin. Under this condition, time-interval to phase III at the duodenal recording site was 30 +/- 13 (SEM) min after Motilin, compared with 79 +/- 14 min after saline (P < 0.01), and compared with 121 +/- 13 min for Motilin infusion following an antral phase III (P < 0.001). Motilin did not affect small intestinal motility or isolated pyloric pressure waves (IPPWs). However, the number of IPPWs was significantly affected by the origin of the preceding phase III, irrespective of whether Motilin or saline was infused. Gallbladder volume decreased significantly within 10 min after each Motilin infusion. We conclude that this study clearly demonstrates differential regional effects of Motilin. Motilin initiates antral phase IIIs, but stimulation is subject to a refractory period which is clearly prolonged after a preceding antral phase III. Motilin induced gallbladder emptying, however, is not subject to a refractory state. Small intestinal phase IIIs as well as pyloric IPPWs are not affected by Motilin.

  • effects of Motilin on human interdigestive gastrointestinal and gallbladder motility and involvement of 5ht3 receptors
    Neurogastroenterology and Motility, 2002
    Co-Authors: Y C Luiking, T L Peeters, L M A Akkermans, P J Cnossen, V B Nieuwenhuijs, G Vanberge P Henegouwen
    Abstract:

    A plasma Motilin peak and a partial gallbladder emptying precede the antral phase III of the migrating motor complex (MMC). To clarify the causal relationship between these factors, we aimed to study the role of Motilin in interdigestive gastrointestinal and gallbladder motility simultaneously. In addition, involvement of 5HT3 receptors in the action of Motilin was studied. Eight fasting, healthy male volunteers received 13Leu-Motilin or 0.9% NaCl i.v. for 30 min, in randomized order on two separate occasions, from 30 min after phase III. Seven of the eight subjects also received the 5HT3 receptor antagonist ondansetron in addition to Motilin, on a third occasion. Antroduodenal motility, gallbladder volumes and plasma Motilin were measured. The interval between the start of infusion and phase III was 95.0 (57.6-155.7) min for saline, 28.7 (21.0-33.2) min for Motilin, and 39.3 (30.7-100.5) min for Motilin + ondansetron (P < 0.05). Gallbladder volume decreased by one-third from 10 min after both Motilin and Motilin + ondansetron infusion (P < 0.05), and returned to baseline with duodenal passage of phase III. In two of the seven subjects phase III was absent after Motilin + ondansetron, although gallbladder volume decreased and only refilled during a later spontaneous phase III. We conclude that Motilin induces both partial gallbladder emptying and antral phase III. Indeed, although gallbladder emptying clearly precedes antral phase III, ondansetron only prevented phase III in some cases and had no effect on gallbladder emptying. Passage of phase III in the duodenum makes an important contribution to gallbladder refilling.

  • Motilin receptor density in inflamed and noninflamed tissue in rabbit tnbs induced colitis
    Neurogastroenterology and Motility, 2001
    Co-Authors: Inge Depoortere, G Van Assche, T L Peeters
    Abstract:

    Trinitrobenzenesulphonic acid (TNBS)-induced colitis decreases the contractile response of the rabbit colon to Motilin, and inflammation may increase plasma Motilin levels. We studied whether the decreased contractility could be due to a down-regulation of Motilin receptors, caused by increased plasma Motilin levels. As this would affect all tissues, uninflamed sites were studied as well. Colitis was induced by different doses (100–150 mg kg−1) of TNBS. In the colon, the TNBS dose-dependent decrease of the contractile response towards Motilin was reflected in a decrease in Motilin receptor density. In contrast, in the antrum, receptors were upregulated by 150 mg kg−1 TNBS, while central Motilin receptors in the cerebellum were not affected. Plasma Motilin levels were not influenced by inflammation, although the Motilin content and mRNA expression in the duodenal and jejunal mucosa, but not in the colon, was significantly increased. The opposite was true for interleukin-1β and interleukin receptor antagonist mRNA expression. We conclude that the decreased Motilin contractility in rabbit colitis is due to a downregulation of Motilin receptors in the colon, but this is not caused by chronic hormonal stimulation.

  • Contractile effects and intracellular Ca2+ signalling induced by Motilin and erythromycin in the circular smooth muscle of human colon
    Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 2001
    Co-Authors: G Van Assche, Theo Thijs, Jozef Janssens, Ludwig Missiaen, Freddy Penninckx, H. Takanashi, K. Geboes, T L Peeters
    Abstract:

    Motilin has excitatory effects on the colon of the rabbit and the dog, but little is known of its effect on the human colon. The aim of this study was to investigate the effects induced by Motilin and erythromycin A (EMA) on muscle strips and on single cells from primary cultures from human colon. Isotonic contraction was recorded in circular muscle strips from macroscopically normal resection specimens of patients operated on for colonic neoplasm. Agonist-induced intracellular Ca2+ ([Ca2+]i) signalling was studied in primary cultures of colonic smooth-muscle cells using the ratiometric Ca2+ indicator Indo 1, on a laser-scanning confocal epifluorescence microscope. In circular muscle strips, norleucine13-porcine Motilin ([Nle13]-pm)and EMA induced tonic contractions with an EC50 of 92 +/- 21 nmol L(-1) and 31 +/- 16 micromol L(-1), respectively. The maximal contraction was 21 +/- 4% (Motilin) and 33 +/- 12% (EMA) of the response to 10(-4) mol L(-1) acetylcholine (ACh). The Motilin antagonist OHM-11526 (10(-5.5) mol L(-1)) abolished the effects of both [Nle13]-pm and EMA. Neither tetrodotoxin (10(-5.5) mol L(-1)), L-nitro-D-arginine methyl ester (L-NAME) (10(-3.5) mol L(-1)) nor guanethidine (10(-5) mol L(-1)) interfered with the effects of [Nle13]-pm or EMA. [Nle13]-pm (10(-11)-10(-6) mol L(-1)) induced rises of [Ca2+]i in cultured colonic myocytes. At 10(-6) mol L-1, 94% of the cells responded, and half of the cells responded at 1.4 nmol L(-1) [Nle13]-pm. 81% (35/43) and 95% (75/79) responded to EMA (10(-6) mol L(-1)) and acetylcholine (ACh, 10(-4) mol L(-1)), respectively. The Motilin antagonist GM-109 inhibited Motilin- and EMA-induced [Ca2+]i rises. In the absence of extracellular Ca2+, only 13% (7/52) of the cells responded to [Nle13]-pm (10(-6) mol L(-1)) vs. 90% (47/52) to ACh (10(-4) mol L(-1)). Motilin and EMA have direct excitatory effects on circular smooth muscle from the human colon and these effects are mediated via a smooth-muscle Motilin receptor. These findings suggest that Motilin may regulate colonic motility and that motilides may have therapeutic potential for the treatment of colonic hypomotility.

  • Motilin induces gall bladder emptying and antral contractions in the fasted state in humans
    Gut, 1998
    Co-Authors: Y C Luiking, Inge Depoortere, T L Peeters, V B Nieuwenhuijs, M F J Stolk, Piero Portincasa, G P Van Berge Henegouwen, L M A Akkermans
    Abstract:

    Background —Animal studies have shown that Motilin affects gall bladder motility. In humans, no effect has been shown, but erythromycin, a Motilin receptor agonist, induces gall bladder emptying. Aims —To explore the effect of increasing doses of exogenous Motilin on gall bladder volume and antral contractility in the fasted state in humans. Methods —After an overnight fast, eight healthy men received increasing intravenous doses of Leu 13 -Motilin (KW-5139) or 0.9% NaCl in a double blind, randomised fashion. Gall bladder volume and antral contraction frequency were determined by ultrasonography. Results —Infusion of Motilin increased plasma Motilin levels. Motilin induced a reduction in gall bladder volume of 8.0 (5.0)%, 17.1 (5.0)%, 18.5 (4.7)%, and 16.1 (4.9)% of baseline volume at the end of infusion of 2, 4, ,8 and 16 pmol/kg/min respectively, compared with mean stable gall bladder volumes during placebo infusion (p Conclusions —Exogenous Motilin reducted fasting gall bladder volume and increased antral contractions. After reaching maximal reduction, the gall bladder volume did not decrease further during continuous Motilin infusion at higher doses and stayed at the same reduced volume. The degree of gall bladder volume reduction during Motilin infusion mimicked gall bladder emptying preceding antral phase III activity of the migrating motor complex in humans. This study indicates that Motilin may play a physiological role in the regulation of gall bladder emptying in the fasted state.