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At least 19 recordsLinked to original sources
PubMed1976

[The synthesis of motilin, III: Purification and characterization of (13-norleucine) motilin and (13-leucine) motilin (author's transl)].

The preparation of the pure docosapeptide H-Phe-Val-Pro-I1e-Phe-Thr-Tyr-Gly-Glu-Leu-Gln-Arg-Nle-Glu-Glu-Lys-Glu-Arg-Asn-Lys-Gly-Gln-OH ([Nle13]motilin) and of the analogous [Leu13]motilin from the crude synthetic materials obtained after deblocking of the overall protected docosapeptide derivatives by means of trifluoroacetic acid is described. In a preliminary experiment the separation of crude [Nle13]-motilin into several components, some of which being indistinguishable by thin layer chromatography, was achieved by repeated ion-exchange chromatography on QAE-Sephadex A-25 and SP-Sephadex C-25. Subsequent characterization of some of the isolated side-products, using amino acid analysis as well as spectroscopic (UV, CD) and enzymatic methods, in comparison to the major product enabled conclusions on the reasons of their formation. The undesired formation of des-(Thr6 -Tyr7 Gly8)[Nle13] motilin and of [D-Phe5-Nle13]motilin could be avoided during the subsequent major synthesis of [Nle13] motilin and during the preparation of [Leu13] motilin by changing certain synthetic conditions and, respectively, by using a specially purified protected fragment of the sequence 1-8, being free of diastereomers. Single ion-exchange chromatography on SP-Sephadex C-25 was sufficient for the purification of the so obtained crude synthetic end-products.

Amino Acids↗
PubMed1976

[The synthesis of motilin, I: Preparation of the sequence fragments 9 - 22 of [13-norleucine]motilin and [13-leucine]motilin (author's transl)].

The syntheses of two suitably protected tetradecapeptides corresponding to the sequences 9 - 22 of [13-norlecucine] motilin [H-Glu(OBut)-Leu-Gln-Arg(HBr)-Nle-Glu(OBut)-Glu(OBut)-Lys(Boc)-Glu(OBut)-Arg(HBr-Asn-Lys(Boc)-Gly-Gln-OBu] and [13-leucine] motilin, respectively, are described. The two building blocks for the total syntheses of the motilin analogs were obtained by fragment-condensation of smaller units, prepared by stepwise procedure and corresponding to the sequences 18 - 22, 14 - 17, 12 - 13 (norleucine- and leucine-derivatives) and 9 - 11.

Amino Acid Sequence↗
PubMed1976

[The synthesis of motilin, II: Preparation of the complete sequences of [13-norleucine] motilin and [13-leucine] motilin (author's transl)].

Syntheses of two analogs of the intestinal hormone motilin containing in position 13 norleucine and leucine, respectively, are described. For this purpose a suitably protected octapeptide-derivative, corresponding to the sequence 1-8, was prepared and condensed with the tetradecapeptides 9-22 of [13-norleucine]-motilin and [13-leucine] motilin (described in the preceding paper) to give to overall protectdd docosapeptides Boc-Phe-Val-Pro-IIe-Phe-Thr-(But)-Tyr(But)-Gly-Glu(OBut)-Leu-Gln-Arg-(HBr)-Nle-Glu(OBut)-Glu(OBut)-Lys(Boc)-Glu-(OBut)-Arg(HBr)-Asn-Lys(Boc)-Gly-Gln-OBut and its 13-leucine analog.

Amino Acid Sequence↗
PubMed2001

Motilin and motilin receptors: characterization and functional significance.

In order to get more insight into the mechanism of action of the gastrointestinal peptide, motilin, and its role in human physiology, we aimed at characterizing motilin and motilin receptors. Motilin. Sequence analysis of the motilin precursor from several species indicated that the N- and C-terminal regions of the motilin precursor have evolved at different rates. Sequence analysis of the motilin precursor in brain tissue of rabbit and man and motilin radioimmunoassay on tissue extracts, proved that motilin is a brain-gut peptide. Plasma motilin levels are increased in patients with ulcerative colitis or Crohn's disease. A weak correlation between the motilin genotype and the susceptibility to inflammatory bowel disease was demonstrated. Motilin receptors. Motilin receptors are expressed early postnatally and can be regulated by changes in its plasma level. The pharmacophore of motilin consists of the aromatic rings from Phe1 and Tyr7 and the aliphatic side chains from Val2 and Ile4. In vivo and in vitro studies showed that in the rabbit and human antrum, smooth muscle and neuronal motilin receptors exist which have different characteristics. In the rabbit duodenum motilin's action depends upon the influx of extra- and intracellular Ca2+. Nevertheless, in primary smooth muscle cultures, Ca2+ influx through L-type Ca2+ channels is the major transduction mechanism. The existence of central motilin receptors was demonstrated by autoradiography. Receptor binding studies allowed the identification of two binding sites. In contrast to antral smooth muscle cells, the response to motilin in the human TE671 medulloblastoma cell line, expressing the motilin receptor, relies on intracellular IP3-sensitive Ca2+ stores. The antibiotic erythromycin-A (EM-A) binds to the motilin receptor and induces contractions with the same regional and species specificity as motilin. This interaction was supported by the discovery of motilin antagonists. Structure activity studies led to the development of more powerful erythromycin derivatives, which lack antibiotic properties and which are now in clinical trial for treatment of hypomotility disorders. Conclusion and perspectives. The physiological role of motilin and its receptors in the brain requires further investigation. Erythromycin and its derivatives act as motilin agonists with clinically useful prokinetic potential. The motilin receptor has recently been cloned and has substantial structural homology with the growth hormone secretagogue receptor. This may not only lead to the further characterization of motilin receptor subtypes and aid the development of safe and selective motilin receptor agonists and antagonists, useful for the treatment of GI disorders, but may also give a new dimension to the role of motilin in human physiology.

Animals↗
PubMed1996

Exogenous motilin stimulates endogenous release of motilin through cholinergic muscarinic pathways in the dog.

BACKGROUND & AIMS: Exogenous motilin is believed to stimulate endogenous release of motilin, but this has not been studied in detail. The aim of this study was to investigate whether and by what mechanism exogenous motilin stimulates endogenous release of motilin in the dog. METHODS: Gastric and duodenal contractile activity in conscious dogs was monitored by chronically implanted force transducers. Plasma canine motilin (c-motilin) concentrations in response to exogenous porcine motilin (p-motilin) were determined by specific radioimmunoassay for c-motilin. The release of motilin from motilin cells obtained from canine duodenal mucosa was studied in vitro using a perifusion system. RESULTS: In vitro, c-motilin release was stimulated by carbachol but not by p-motilin, and the carbachol-induced c-motilin release was inhibited by atropine. In vivo, exogenous p-motilin stimulated endogenous c-motilin release and gastric and duodenal phase III-like contractions; this motilin-induced motilin release was inhibited by atropine, hexamethonium, and a 5-hydroxy-tryptamine 3 receptor antagonist. CONCLUSIONS: In the dog, exogenous motilin stimulates endogenous motilin release through muscarinic receptors on motilin-producing cells via preganglionic pathways involving 5-hydroxytryptamine 3 receptors.

Amino Acid Sequence↗
PubMed1984

Relationship between porcine motilin-induced migrating motor complex-like activity, vagal integrity, and endogenous motilin release in dogs.

Both the vagus nerve and motilin have been implicated in the initiation of phase III of the fasting migrating motor complex. To investigate the contribution of each, the effects of intravenous porcine motilin, vagosympathetic nerve blockade, and atropine were assessed. Intralumenal pressures of the lower esophageal sphincter, stomach, and upper small intestine, and plasma motilin levels were monitored. Porcine and canine motilin in plasma were distinguished by radioimmunoassay using two different antibodies. Injection of porcine motilin (75-370 pmol), initiated dose-dependent phase III-like motor activity in the lower esophageal sphincter, stomach, and small bowel if the vagi were intact; if the vagi were blocked, activity was initiated in the small bowel only. Moreover , a significant (p less than 0.001), dose-dependent peak in canine plasma motilin was observed after the onset of the induced motor activity when the vagi were intact or blocked, with plasma motilin peaks comparable to those occurring spontaneously. In both intact and vagally blocked dogs, atropine abolished both the spontaneous motor activity and associated rise in motilin level, and also abolished porcine motilin-induced activity. However, a diminished, but significant (p less than 0.01) peak in porcine motilin-induced canine motilin persisted in the presence of atropine. These results in dogs indicate that while spontaneous phase II motility in the upper gastrointestinal tract and phase III activity in the lower esophageal sphincter and stomach are dependent on vagally mediated excitatory pathways, spontaneous and induced phase III motor activity in the small intestine are dependent on nonvagal cholinergic innervation. Canine motilin release induced by porcine motilin is mediated primarily by a nonvagal cholinergic (muscarinic) pathway, with minor contributions from vagal noncholinergic, and nonvagal noncholinergic mechanisms. Because spontaneous or induced motilin release peaks well after the onset of phase III motor activity, it is unlikely that motilin is the primary factor responsible for initiation of the migrating motor complex in the dog. Motilin may, however, modulate motility produced by preexisting neural excitation.

Animals↗
PubMed2006

[Evidence for the presence of motilin receptor and a study on the mechanism of motilin induced Ca2+ signaling in rat myenteric neurons].

OBJECTIVE: To observe whether the motilin receptor (MTLR) can be expressed in primarily cultured myenteric neurons of rats and investigate the mechanism of motilin induced Ca2+ signaling in myenteric neurons of rats. METHODS: Expression of the motilin receptor was identified with double-immunofluorescence staining technique. Data on the intracellular Ca2+ concentration ([Ca2+]i) of cultured myenteric neurons with different treatments were collected by measuring Ca2+ fluorescent intensity (FI) in each neuron under confocal microscope. RESULTS: The cultured myenteric neurons showed positive motilin receptor immunoreactivity. In Hank's solution, 10(-6) mol/L motilin could elevate [Ca2+]i, its height of peak being 30.6 +/- 3.7 and its FI relative change percentage being (100. 8 +/- 18.4)%. In D-Hank's solution (after removal of extracellular Ca2+, or after treatment with verapamil,an L-type calcium channel blocker), motilin could induce a small increase of [Ca2+]i. After pretreatment with NEM,a G protein inhibitor, and Compound 48/80, a PLC inhibitor, in Hank's solution respectively, motilin was inhibited and the [Ca2+]i was significantly lower than that of the group to which was added only motilin (P < 0.05). After pretreatment with D-sphingosine, a PKC inhibitor, the effect of motilin was not significantly different from that of the group to which was added only motilin (P > 0.05). CONCLUSION: The motilin receptor could be expressed by cultured myenteric neurons of rats. Motilin could increase [Ca+]i. The increase of [Ca2+]i was caused by release of intracellular stores and influx of extracellular Ca2+, mainly through the L-type calcium channel. The motilin receptor-coupled G-protein, PLC and IP3 pathway participated in the release of Ca2+ from intracellular stores.

Animals↗
PubMed1994

Motilin synthetic analogues and motilin receptor antagonists.

While studying the structure-activity characteristics of motilin with motilin synthetic analogues, two compounds, motilin 1-12 [CH2 NH]3-4 and motilin 1-12 [CH2 NH]10-11, showed high affinity for the motilin receptor combined to a weak contractile activity. The following data suggest that motilin 1-12 [CH2 NH]10-11 is a potent motilin receptor antagonist. It showed a high affinity for the motilin receptor present on membranes of rabbit antrum (pIC50: 8.24 +/- 0.08 for the analogue vs 8.96 +/- 0.02 for the native peptide). When tested in vitro on strips of rabbit duodenum, the dose-response curve to motilin 1-22 was displaced to the right with motilin 1-12 [CH2 NH]10-11 (pIC50: 8.91 +/- 0.06 in presence of saline versus 7.19 +/- 0.40 with the analogue). However, when injected i.v. in dogs, motilin 1-12 [CH2 NH]10-11 was undetectable in the peripheral blood, suggesting enzymatic degradation precluding its use in vivo.

Animals↗
PubMed2000

Peripheral or central administration of motilin suppresses LH release in female rats: a novel role for motilin.

Motilin is secreted in a clear episodic pattern during fasting or during the interdigestive phase, but feeding promptly stops this secretory pattern, and plasma concentrations of motilin decrease. We have previously determined that fasting markedly suppresses pulsatile luteinizing hormone (LH) secretion in female rats in the presence of oestrogen. In the present study, we wished to learn if motilin may mediate the fasting-induced suppression of LH secretion by determining the effects of motilin administration on LH release and on food intake. Intravenous (i.v.) injection of motilin (37 nmol/rat) suppressed LH release and significantly decreased mean LH concentrations both in ovariectomized (OVX) and oestradiol-implanted ovariectomized (OVX+E2) rats. Food intake was significantly increased by i.v. motilin injection in OVX rats, but not in OVX+E2 rats. It is likely that motilin inhibits LH release via inhibition of the gonadotrophin-releasing hormone (GnRH)-releasing mechanism at the hypothalamic level, because motilin (3.7 nmol/rat) also suppressed LH secretion when centrally administered, and because LH release in i.v. motilin-treated rats increased in response to exogenous GnRH. These results suggest that motilin may be a peripheral signal for the suppression of LH secretion through central sensors.

Animals↗
PubMed1996

[Motilin and motilin receptor].

Motilin, a 22 amino acid polypeptide, is known to play an important role in the initiation of phase III activity of the interdigestive migrating contractions (IMC) in the dog and man. The precursor of human motilin consists of 115 amino acids including a 25 amino acid signal peptide in direct linkage with the 22 amino acid motilin sequence and a 66 amino acid carboxy-terminal motilin-associated peptide (MAP). Northern blot analysis revealed that motilin mRNA is abundant in the duodenum. In vitro studies suggested that motilin acts directly on motilin receptors located on gastrointestinal smooth muscle cells in the rabbit, cat and man. On the contrary, in vivo studies suggested that motilin receptors are likely to be present in the nervous system. The cloning of motilin receptors is needed to clarify the detailed mechanism(s) of motilin's action.

Amino Acid Sequence↗
PubMed2005

Motilin and erythromycin-A share a common binding site in the third transmembrane segment of the motilin receptor.

UNLABELLED: 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 E119 located in the third transmembrane (TM3) 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 Ca2+ indicator apo-aequorin. Receptor activation in response to motilin, EM-A and their analogues was assessed by Ca2+-luminescense. RESULTS: In the E119Q mutant, the Ca2+ response to motilin and EM-A was abolished while in the E119D mutant it was reduced with 62% (motilin) and 81% (EM-A). The pEC50 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 TM3 domain of the MTLR. The results with acetylated derivatives support an ionic interaction between E119 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.

Amino Acid Sequence↗
PubMed2006

Delineation of the motilin domain involved in desensitization and internalization of the motilin receptor by using full and partial antagonists.

UNLABELLED: Studies with fragments of the gastrointestinal peptide, motilin, indicate that the C-terminal region of this peptide plays an important role in the desensitization of the motilin receptor (MTLR). AIM: To verify this hypothesis we studied the desensitization, phosphorylation and internalization induced by motilin analogues of different chain length with agonistic and antagonistic properties in CHO-MTLR cells. METHODS: We studied motilin [1-22], the [1-14] fragment, the analogues Phe(3)[1-22] and Phe(3)[1-14], and two putative antagonists, GM-109 and MA-2029 (modified 1-4 and 1-3 fragments). Activation and desensitization (2h preincubation with the motilin analogues 10muM) were studied in CHO-MTLR cells by an aequorin based luminescence assay. Phosphorylation was studied by immunoprecipitation and internalization was visualized in CHO-MTLR cells containing an enhanced green fluorescent protein (CHO-MTLR-EGFP). RESULTS: Motilin [1-22] and [1-14] were more potent than Phe(3)[1-22] and Phe(3)[1-14] (pEC(50): 9.77, 8.78, 7.36 and 6.65, respectively) to induce Ca(2+) release. GM-109 and MA-2029 were without agonist activity. [1-22] and Phe(3)[1-22] decreased the second response to motilin from 78+/-2% to 11+/-3% and 34+/-3% (P<0.001), respectively, whereas [1-14], Phe(3)[1-14], GM-109 and MA-2029 had no desensitizing effect (68+/-5%, 78+/-3%, 78+/-6% and 78+/-5%, respectively, P>0.05). The rank order of MTLR-phosphorylation was: [1-22]>[1-14]>Phe(3)[1-22]=Phe(3)[1-14]>GM-109=MA-2029. Only motilin [1-22] and [1-14] induced receptor MTLR-EGFP internalization as shown by a decrease in membrane fluorescence: 20+/-3% and 7+/-3%, respectively. CONCLUSION: The C-terminus of motilin enhances desensitization, phosphorylation and internalization of the MTLR while modifications of the N-terminus can favor a conformation of the receptor that is less susceptible to phosphorylation and internalization.

Animals↗
PubMed2005

Evidence for the presence of motilin, ghrelin, and the motilin and ghrelin receptor in neurons of the myenteric plexus.

Motilin, a 22-amino acid gastrointestinal peptide, and ghrelin, the natural ligand of the growth hormone secretagogue receptor, form a new group of structurally related peptides. Several lines of evidence suggest that motilin and ghrelin are involved in the control of gastrointestinal motility by the activation of receptors on enteric neurons. The aim of this study was to look for the existence of motilin, ghrelin, and their respective receptors in the myenteric plexus of the guinea pig. We used longitudinal muscle/myenteric plexus (LMMP) preparations and cultures of myenteric neurons of the guinea pig ileum, immunohistochemistry, and reverse transcriptase-polymerase chain reaction (RT-PCR). Most of the motilin-immunoreactive (IR; 72.8%) and motilin receptor-IR (68.9%) neurons were also positive for neuronal nitric oxide synthase (nNOS), 72.8% and 68.9%, few for choline acetyl transferase (ChAT), 11.4% and 11.9%, respectively. In contrast, ghrelin was mainly colocalized with ChAT (72.2%), and only 3.6% of ghrelin-positive cells showed nNOS-IR in the LMMP. Neither motilin nor the motilin receptor or ghrelin colocalized with calbindin. RT-PCR studies revealed motilin, ghrelin, and ghrelin receptor mRNA transcripts in LMMP preparations and in cultured myenteric neurons. In conclusion, this study, for the first time, provides direct evidence for the existence of motilin and ghrelin in myenteric neurons and suggests that both peptides may play a role in the activation of the enteric nervous system and hence in the regulation of gastrointestinal motility.

Animals↗
PubMed1998

Anxiolytic effect of motilin and reversal with GM-109, a motilin antagonist, in mice.

There have been few reports on the effects of the brain-gut peptide motilin on the central nervous system (CNS). We administered motilin intracerebroventricularly to mice and investigated the effect of motilin on anxiety using an elevated plus-maze. Motilin produced a significant decrease in anxiety with an inverted U-shaped dose response. To determine whether the anxiolytic effect of motilin was mediated via motilin receptors in the brain, the effect of GM-109, a novel motilin receptor antagonist, was investigated. GM-109 showed a significant and dose-dependent antagonism on the motilin-induced anxiolytic effect. GM-109 administered alone had no effect on anxiety. These results suggest that motilin receptors are present in the brain and may have a role in anxiety and emotion.

Animals↗
PubMed1987

Comparative stimulation of motilin duodenal receptor by porcine or canine motilin.

Motilins purified from porcine and canine intestine differ in their amino acid composition in positions 7-8-12-13-14. We studied in vitro the contractile response of longitudinal duodenal muscles from various animals (guinea pig, rabbit, dog) to porcine and canine synthetic motilins. Both substances failed to elicit contraction of the guinea pig duodenum but were active and equally potent on rabbit muscle. In dogs, porcine motilin was inactive at the concentrations tested (up to 10(-4) M) whereas canine motilin induced duodenal contractions in a dose-response fashion (mean dose required to induce half-maximal response: 4.82 +/- 0.25 X 10(-5) M). The contraction generated by synthetic canine motilin (10(-5) M) was not influenced by atropine, hexamethonium, tetrodotoxin, naloxone, or sodium nitroprusside (all used at 10(-4) M) but was blocked by verapamil (10(-4)). Our study shows that species-related structural alterations in motilin molecules generate different bioactive capacities in some animal species, suggests that the middle portion of the molecule is important for its bioactive expression, suggests the presence of motilin receptors on canine duodenal muscle, and suggests that an influx of extracellular calcium is involved in the canine duodenal muscle contraction elicited by canine motilin.

Animals↗
PubMed1997

Identification of motilin mRNA in the brain of man and rabbit. Conservation of polymorphism of the motilin gene across species.

The data regarding the identity of motilin-like immunoreactivity in the central nervous system are controversial. The aim of the present study was to clarify whether motilin mRNA is present in the brain of rabbit and man. Total RNA, prepared from several regions of the rabbit brain, was subjected to RT-PCR aimed at amplifying a 294 bp cDNA fragment of the rabbit motilin precursor. The amplified product was subcloned and sequenced. The sequence showed 7 differences compared to the one reported for the duodenal precursor (1). However the duodenal precursor from the rabbit used in the present study revealed identical substitutions. One of these, involving amino acid -11 of the signal peptide, was shown to be due to gene polymorphism, as has also been described at this site in man. By radioimmunoassay the highest concentration of motilin (fmol/mg protein) was detected in the hippocampus (4788 +/- 295), the lowest in the telencephalon (2127 +/- 221). Using a similar approach, but starting from commercial human brain mRNA, the sequence of a comparable cDNA fragment of the human brain motilin precursor was obtained. Its sequence was identical with the one published for the human intestinal precursor (41). Our study demonstrates that motilin mRNA is present in the brain of man and rabbit. Together with our recent findings of central motilin receptors, they suggest a central role for motilin.

Amino Acid Sequence↗
PubMed1991

Motilin-immunoreactive cells in the duodenum, pyloric stomach and pancreas of caimans (Caiman latirostris and Caiman crocodilus, alligatorinae): a further comparison using region-specific motilin antisera.

Motilin-immunoreactive cells in the duodenum, pyloric stomach and pancreas of Caiman latirostris and Caiman crocodilus were investigated using region specific antisera for porcine and canine motilin molecules. Motilin-immunoreactive cells were found in the duodenum, pyloric stomach and pancreas of both caiman species. These cells were primarily open-type endocrine ones in the epithelium of the duodenum and pyloric stomach. Motilin-immunoreactive cells were observed in both the exocrine and endocrine portions of the pancreas, and frequently exhibited one or more cytoplasmic processes of variable length. Since motilin-immunoreactive cells do not cross-react with serotonin or any of the other pancreatic and gut hormones, they are considered to be cell type independent from any of the other known pancreatic or gut endocrine cells. The molecular similarity between caiman motilin and porcine and canine motilins and the heterogeneity of the motilin molecule in the caiman digestive system is discussed.

Alligators and Crocodiles↗