Motilin receptors in the human antrum
Paul
Miller1,
André
Roy2,
Serge
St-Pierre3,
Michel
Dagenais2,
Réal
Lapointe2, and
Pierre
Poitras1
1 Gastrointestinal Unit and 2 Department of
Surgery, Centre Hospitalier de l'Université de
Montréal; and 3 Department of Chemistry,
Université du Québec à Montréal, Montreal,
Quebec, Canada H2X 3J4
 |
ABSTRACT |
Motilin is an intestinal peptide that
stimulates contraction of gut smooth muscle. The motilin receptor has
not been cloned yet, but motilin-receptor agonists appear to be potent
prokinetic agents for the treatment of dysmotility disorders. The aim
of this study was to determine neural or muscular localization of motilin receptors in human upper gastrointestinal tract and to investigate their pharmacological characteristics. The binding of
125I-labeled motilin to tissue membranes prepared from
human stomach and duodenum was studied; rabbit tissues were used for
comparison. Solutions enriched in neural synaptosomes or in smooth
muscle plasma membranes were obtained. Various motilin analogs were
used to displace the motilin radioligand from the various tissue
membranes. The highest concentration of human motilin receptors was
found in the antrum, predominantly in the neural preparation. Human motilin receptors were sensitive to the NH2-terminal
portion of the motilin molecule, but comparison with rabbit showed that
both species had specific affinities for various motilin analogs
[i.e., Mot-(1
9), Mot-(1
12), Mot-(1
12)
(CH2NH)10-11, and erythromycin]. Motilin receptors obtained from synaptosomes or muscular plasma membranes of human antrum expressed different affinity for two motilin-receptor agonists, Mot-(1
12) and Mot-(1
12)
(CH2NH)10-11, suggesting that they
correspond to specific receptor subtypes. We conclude that human
motilin receptors are located predominantly in nerves of the antral
wall, are functionally (and probably structurally) different from those
found in other species such as the rabbit, and express specific
functional (and probably structural) characteristics dependent on their
localization on antral nerves or muscles, suggesting the existence of
specific receptor subtypes, potentially of significant physiological or
pharmacological relevance.
gastrointestinal motility; regulatory peptides; receptor subtypes
 |
INTRODUCTION |
MOTILIN IS A 22-amino acid peptide synthesized by
endocrine cells of the duodenojejunal mucosa that stimulates the
contraction of smooth muscles of the gastrointestinal tract (for
review, see Ref. 23). Motilin appears as a circulating hormone
controlling the interdigestive motility of the gastroduodenal tract
through cyclic increases in circulating plasma motilin that regulate
the phase III contraction of the migrating motor complex in the upper gut (4, 23, 24).
Motilin receptors were identified mostly in the upper part of the
digestive tract. Motilin-induced contraction seems to involve both a
direct action on the smooth muscle cell and/or a neural mediation
through various neurotransmitters, such as acetylcholine. Motilin
receptors can be activated by motilin and by motilin synthetic analogs
constructed from the NH2-terminal portion of the native molecule (18, 25). Motilin receptors can also be activated by macrolide
compounds derived from erythromycin (16, 22). Erythromycin and some
derivatives, called motilides (named for their ability to act on
motilin receptors), can indeed mimic the intestinal contraction induced
by motilin. In fact, motilin receptor activation currently represents
the most potent pharmacological stimulus for gastric contraction in
humans. Since the discovery in 1990 by Janssens et al. (15) that
erythromycin could rapidly empty the stomach of diabetics suffering
from severe gastroparesis resistant to usual prokinetic therapy,
motilin-receptor agonists are now considered the most potent
gastrokinetic drugs and, although clinicians use erythromycin in
various hypokinetic digestive disorders (for review, see Ref. 20), many
pharmaceutical companies have worked to develop motilide compounds.
These erythromycin derivatives, with a very high affinity for motilin
receptors but devoid of antibiotic activity, are therefore capable of
stimulating digestive motor activity; some of them have already been
tested in clinical trials.
Characterization of the motilin receptor is very important, among other
things, for the optimal design of motilides to be used for the
treatment of patients with various clinical disorders due to
dysmotility of the digestive tract. This study aims to determine the
localization of motilin receptors on muscle or on neural cells of the
human stomach and to explore the functional characteristics of the
human motilin receptor.
 |
MATERIALS AND METHODS |
Tissue preparation: purification of enriched muscular and neuronal
fractions from human and rabbit tissues.
Human stomachs and duodena were obtained from organ donors. Rabbit
antral smooth muscle tissue was obtained from female albino rabbits
(2.5 kg) that were killed by intravenous pentobarbital injections.
Smooth muscular tissue was dissected away from mucosa using a scalpel
blade (antrum, corpus, and fundus) or with tweezers (duodenum) and
washed in physiological saline solution. Human tissues were stored at
70°C.
Human and rabbit neural and muscular membranes were partially purified
by a modification of the methods of Ahmad et al. (1, 2) used for
purification of canine muscular and neural fractions. All purification
steps were carried out at 4°C. Isolated smooth muscle tissues from
antrum, corpus, fundus, and duodenum were minced and homogenized
separately in 12 volumes of ice-cold homogenization buffer (50 mM Tris,
10 mM MgCl2, 1 mM EDTA, and 0.25 M sucrose, pH 8.0) in a
Brinkmann polytron (PTA20 probe, setting 4, 3 × 8 s; Brinkmann,
Lucerne, Switzerland). Homogenates were initially centrifuged at 1,500 g for 10 min, the pellet was discarded, and the supernatants
(postnuclear supernatant, PNS) were immediately subjected to
centrifugation at 170,000 g for 65 min. The supernatant containing the soluble protein fraction was discarded, and the pellet
was resuspended manually in ice-cold homogenization buffer using a
Potter apparatus. This suspension was centrifuged at 18,000 g
for 10 min. The pellet [mitochondrial (Mit) fraction] and
the supernatant [microsomal (Mic) fraction] were collected.
The Mit fraction was resuspended manually in ice-cold homogenization
buffer using a Potter apparatus.
The PNS, Mit, and Mic were assayed for saxitoxin binding to determine
neural membrane content, for 5'nucleotidase (5'N) activity to determine smooth muscle membrane content, and for total membrane protein.
Binding assay.
Porcine Mot-(1
22) was iodinated by the chloramine-T method and
purified by HPLC. The mean radiospecific activity was ~1,000 cpm/fmol
as determined by the RIA self-displacement method.
Binding of 125I-labeled motilin was performed on partially
purified membrane extracts (Mit and Mic) in a total volume of 500 µl
of 50 mM Tris · HCl (pH 8.0), 1 mM EDTA, 10 mM
MgCl2, and 2% BSA at 30°C for 60 min. Membranes were
harvested by aspiration onto presoaked filters (Whatman glass fiber
filters type F, 10 % BSA in H2O, frozen at
20°C
for 24 h) and washed with 25 ml of washing buffer (50 mM
Tris · HCl, pH 8.0, 1 mM EDTA, and 10 mM
MgCl2). The radioactivity was determined in a gamma
counter. Specific binding of 125I-motilin was calculated
from total and nonspecific binding determined in the absence and
presence of 10
6 M porcine motilin.
Nonspecific binding represented roughly 15-50% of total binding.
Maximal binding capacity in the human antral Mit fraction was
determined in hot saturation experiments using 0.15-14.7 nM free
concentrations of 125I-motilin. The maximal binding
capacities of the human corpus, fundus, and duodenum were determined by
cold saturation analysis of competition studies using INPLOT 4.0.
Competition binding studies were performed with a concentration of 2 nM
125I-motilin (human tissues) and 1 nM
125I-motilin (rabbit tissues). Competition binding
experiments were performed in human and rabbit antral fractions to
determine the receptor affinity for various NH2-terminal
analogs of motilin, including Mot-(1
22), Mot-(1
19), Mot-(1
15),
Mot-(1
12), Mot-(1
9), erythromycin, and the motilin antagonist
Mot-(1
12) (CH2NH)10-11. The
concentration of analog that displaced 50% of the labeled motilin
(IC50) was determined. The IC50 is referred to
in the text and graphs as the pIC50, indicating the
negative logarithm of IC50.
All analogs of motilin, including porcine (or human) synthetic
Mot-(1
22), Mot-(1
19), Mot-(1
15), Mot-(1
12), and Mot-(1
9) and
the motilin analog Mot-(1
12)
(CH2NH)10-11, used in this study were
assembled in the laboratory of Dr. S. St-Pierre (Pte. Claire, PQ,
Canada). Erythromycin lactobionate was purchased from Abbott
Laboratories, (Montreal, PQ, Canada).
Data analysis.
All binding data were analyzed for linear or nonlinear regression using
INPLOT 4.0. Binding data among different fractions were compared by
Student's t-test.
 |
RESULTS |
Distribution of motilin receptors in human intestinal tissues
(antrum, corpus, fundus, and duodenum).
Values for 5'N activity and [3H]saxitoxin
binding in centrifugation-prepared human tissue fractions are shown in
Table 1. In the Mic fraction, the
concentration of 5'N increased five times over the basal levels
found in the PNS, whereas the concentration of saxitoxin was only
doubled. In the Mit fraction, 5'N increased five times, but a
13-fold increase in saxitoxin binding was obtained. We therefore
considered that Mic and Mit fractions represented solutions enriched in
muscle (Mic fraction) and in neural (Mit fraction) elements,
respectively. The affinity for 125I-motilin and the binding
capacity in these tissues are also shown in Table 1. Motilin binding
could be detected in both nerve (Mit)- and muscle (Mic)- enriched
solutions of the antrum but only in neural fractions of the corpus,
fundus, and duodenum. The concentration of motilin receptor
(251.9 ± 27.9 fmol/mg) in the antral synaptosomes exceeded
by far the concentration detected in the other tissue preparations.
Figure 1 graphically represents the
relative distribution of motilin binding in correlation with 5'N
activity and saxitoxin binding in the partially purified fractions of
the human antrum.

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Fig. 1.
Relative distribution of motilin (MOT) binding capacity in correlation
with 5'nucleotidase (5'N) activity and saxitoxin (SAX)
binding sites in centrifugation-prepared solutions of human antrum.
PNS, supernatant; Mit, mitochondrial fraction; Mic, microsomal
fraction.
|
|
A hot saturation analysis performed on human antral Mit fractions
enriched in synaptosomes is shown in Fig.
2. The Scatchard analysis (Fig. 2,
inset) reveals a single binding site with a dissociation
constant value of 6.45 nM and a maximum binding capacity of 251.9 ± 27.9 fmol/mg. Competition displacement curves for human antral Mit
fractions are shown in Fig. 3 for
Mot-(1
22), Mot-(1
12), and Mot-(1
12)
(CH2NH)10-11.

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Fig. 2.
From human antral mitochondrial fractions, hot saturation analysis and
Scatchard analysis (inset), revealing a single binding site and
a maximum motilin-binding capacity of 251.9 ± 27.9 fmol/mg.
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Fig. 3.
Competition displacement curves for motilin [Mot-(1 22)],
motilin fragment Mot-(1 12), and motilin antagonist Mot-(1 12)
(CH2NH)10-11 in mitochondrial fractions
prepared from human antrum.
|
|
Analysis of motilin binding in human and rabbit antral nerve
fractions.
Partially purified Mit fractions from human and rabbit antrum were
analyzed for receptor affinity and specificity of binding to various
motilin fragments. Affinity (pIC50) was similar in the
human and rabbit Mit fractions for Mot-(1
22) (9.00 ± 0.02 vs. 9.00 ± 0.03; not significant), Mot-(1
19) (9.20 ± 0.02 vs. 9.01 ± 0.08; not significant), and Mot-(1
15) (8.74 ± 0.06 vs. 8.86 ± 0.05, not significant), but it was significantly lower in
human Mit fractions compared with rabbit Mit fractions for Mot-(1
12)
(7.37 ± 0.03 vs. 8.28 ± 0.22; P = 0.0002) and Mot-(1
9) (3.49 ± 0.03 vs. 5.55 ± 0.12; P < 0.0001; Fig.
4). Erythromycin (6.09 ± 0.03 vs. 6.52 ± 0.04; P < 0.0001) and the motilin antagonist Mot-(1
12)
(CH2NH)10-11 (6.05 ± 0.05 vs. 7.67 ± 0.12; P < 0.0001) also showed lower affinity in human than in
rabbit tissues.

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Fig. 4.
Comparison of tissue affinity from rabbit or from human antrum for
Mot-(1 22), Mot-(1 19), Mot-(1 12), Mot-(1 9), erythromycin
(ERYTH), and Mot-(1 12) (CH2NH)10-11.
* P < 0.001.
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|
Analysis of motilin binding in human antral nerve and muscle
fractions.
To make sure that the data were absolutely comparable, antral Mic and
Mit fractions from the same human specimens were tested in the same
assay with the same analogs in a paired study. The pIC50 of
Mot-(1
22) was similar in both prepared fractions (9.00 ± 0.02 and
9.02 ± 0.04, respectively; not significant, n = 6), but
significantly lower in Mic (muscle-enriched solution) compared with Mit
(neural synaptosome-enriched solution) fractions for Mot-(1
12) (6.36 ± 0.13 vs. 7.63 ± 0.08; P = 0.0007, n = 3) and for
the antagonist Mot-(1
12) (CH2NH)10-11
(5.47 ± 0.06 vs. 6.07 ± 0.04; P < 0.0001, n = 4;
Fig. 5).

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Fig. 5.
Binding affinity of synaptosome-enriched mitochondrial fractions and of
plasma membrane microsomal fractions for Mot-(1 22), Mot-(1 12), and
Mot-(1 12) (CH2NH)10-11. * P < 0.001.
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 |
DISCUSSION |
This study shows that 1) motilin receptors are in maximum
concentration in the antrum of the stomach, 2) they are present on antral muscles, but they can be found predominantly in the neural
structures of the antral wall, 3) the human motilin receptor recognizes the NH2-terminal structure of the motilin
molecule, as previously demonstrated in the rabbit, 4) human
and rabbit motilin receptors are functionally (and probably
structurally) heterogeneous, and 5) motilin receptors in neural
or in muscular membranes of the human antrum express different
affinities for various motilin-receptor agonists and antagonists,
therefore suggesting the existence of a heterogeneity of specific
receptor subtypes.
Our finding that motilin receptors are predominantly located in the
antrum are in agreement with all data published on this topic in humans
and in other species. Peeters et al. (21) previously reported high
binding capacity of the radiolabeled ligand by the human antrum and
proximal duodenum, with a rapidly decreasing gradient along the more
distal small intestine. In our experimental protocol, we did not
differentiate the proximal or distal portions of the human duodenum,
and this could possibly explain the low concentration of motilin
receptors we found in the human duodenum. Motilin receptors have also
been detected in the colon (5, 9) and outside of the digestive tract,
such as in the central nervous system (8) or in vascular arterial
vessels (14). These receptors are still of unknown physiological
significance and were not considered in our study.
Although the specific localization of motilin receptors on nerves or
muscles has been strongly debated in the past, this study reveals
significant information about this topic. First, data obtained on
smooth muscle strips of rabbit or human intestines tested in vitro (30)
clearly showed that the contractile action of motilin could be obtained
through the stimulation of a muscle receptor because the biological
effect was always persistent in the presence of neurological
inhibitors, including tetrodotoxin, a blocker of axonal conductance.
Further studies with isolated muscle cells contracting in response to
motilin or with histochemical localization of 125I-motilin
binding to muscular coats of the intestinal wall brought additional
support to the existence of a motilin receptor located on intestinal
muscle cells (11). However, studies in dog, in vivo as well as in
vitro, clearly indicated that, in this species, motilin-induced
contraction was mediated through neural mechanisms, mostly through
muscarinic influence (13, 29) and possibly by vagal mechanisms (10,
12). The concept of a motilin receptor present on intestinal nerves was
then clearly recognized in human as in rabbit. In in vitro rabbit
studies (27), purification of neural synaptosomes or muscular plasma
membranes from antrum and duodenum (as we did in this study with human
antral tissue) revealed data that suggested the presence of motilin
receptors located predominantly on nerves in the rabbit antrum but on
muscles in the rabbit duodenum. In studies on the ex vivo rabbit
stomach (17), the motor effect of motilin was inhibited by blocking muscarinic transmission with atropine. In a very elegant study on the
contraction of the rabbit stomach in vitro, Parkman et al. (19) showed
that the effect of the motilin-receptor agonist erythromycin was
obtained through two distinct receptors; one neural receptor was
responsible for a chronotropic effect, and the other one, located on
the muscle, had an inotropic action. Similar conclusions were obtained
in humans in which we have shown that the phase III contractions
induced in the antrum by intravenous motilin administration were
blocked by the muscarinic antagonist atropine (3). More recently,
Coulie et al. (6) published studies in conscious volunteers in which
the phase III contractions induced by erythromycin during the fasting
state could be blocked by atropine, which left intact the direct antral
muscular stimulation obtained by using higher doses of erythromycin
after a meal. The current binding study with human tissue is the first
analysis of motilin receptors from human antral nerves.
Characterization of the motilin receptor has been obtained up to now in
the rabbit, in which binding studies could be coupled with functional
experiments. It has been well documented that the bioactive portion of
human motilin relied on the NH2-terminal amino acid
sequence of the molecule when tested on strips of rabbit duodenum in
vitro (25). Binding studies on rabbit antral membranes confirmed the
affinity of the rabbit receptor for the NH2-terminal motilin analogs (18). The current results confirm that the human receptor also expresses affinity for the NH2-terminal
molecular sequence. However, the data obtained with the
NH2-terminal motilin fragments also suggest heterogeneity
between human and rabbit receptors. Indeed, as shown in Fig. 4, the
receptor affinity of human or rabbit receptors for Mot-(1
22) and for
motilin fragments Mot-(1
19) and Mot-(1
15) was similar, but it was
different for shorter peptides such as Mot-(1
12) and Mot-(1
9).
Moreover, the receptor affinity for the motilin antagonist Mot-(1
12)
(CH2NH)10-11 (28), as well as for the
motilin agonist erythromycin, was also different in the two species.
These specific functional characteristics suggest structural
heterogeneity for human and rabbit motilin receptors. This type of
species-specific heterogeneity in the structure of motilin receptors
has already been suspected because experimental reports have previously
demonstrated significant differences in motilin analog activity in
different species. For example,
[Phe3,Leu13]Mot-(1
22) is a
motilin-receptor antagonist in rabbit and in humans but is an important
agonist when tested in the chicken (7). Therefore, species
heterogeneity of motilin receptors should probably be considered in the
pharmaceutical development of motilin-receptor agonists.
The most interesting observation in our study probably concerns the
concept of receptor subtypes in the same species and more particularly
in the same organ. We first suspected this condition in the dog, where
in vivo data (29) revealed the existence of a neural receptor equally
and highly sensitive to human and canine motilins (22-amino acid
peptides with structural variations in positions 7, 8, 12, 13, and 14)
but in which in vitro data (26) suggested the presence of a
muscle receptor sensitive exclusively to the structure of canine
motilin. More recently, in binding studies on rabbit tissues (27), we
observed that the receptor affinity toward various motilin analogs was
different for receptors found in a synaptosome-enriched solution from
the antrum than for receptors present in a plasma membrane-enriched
solution from the duodenum. It was not possible, in that experimental
series, to determine if the documented difference was simply due to the different organs selected (stomach vs. duodenum) or to the specific organelles prepared (nerve vs. muscle). In the current study, we were
able to prepare synaptosome- and plasma membrane-enriched solutions
from the same antrum and to compare both tissue preparations in the
same assay. The affinity for Mot-(1
22) was similar in both fractions,
but the affinity for Mot-(1
12), as for motilin antagonist Mot-(1
12)
(CH2NH)10-11, was clearly different, suggesting therefore that the motilin receptors on neural and muscular
tissues were different. The presence of motilin receptor subtypes,
muscular and neural, was also well supported in functional studies
realized in rabbits as well as in humans. Parkman et al. (19), in the
rabbit in vitro, demonstrated clearly that erythromycin could act via
two different mechanisms: an inotropic effect was obtained via motilin
receptors localized on muscles, and a chronotropic effect was seen at
lower doses and was due to motilin receptors localized on cholinergic
nerves. In humans, Coulie et al. (6) showed that the antral phase III
contractions induced by low doses of erythromycin was inhibited by
atropine, whereas the antral postprandial motor stimulation seen with
high doses of erythromycin was independent of a muscarinic mediation
and therefore could probably be due to a direct muscular effect of
erythromycin. Both functional studies in humans (6) or in rabbits (19)
suggested that the neural receptor was more sensitive than the muscle
receptor to stimulation by erythromycin.
Erythromycin has already been shown to be a strong prokinetic agent and
is currently being used by many clinicians for the management of some
patients with gastroparesis or other dysmotility disorders (20).
Motilin-receptor agonists derived from erythromycin, called motilides,
have been developed, and some of them have already been tested in
clinical trials. Further characterization of motilin receptors would
eventually help to design and develop more specific and potent receptor
agonists to be used in clinical practice to stimulate gastrointestinal
motor activity.
 |
FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: P. Poitras,
Centre Hospitalier de l'Université de Montréal, Saint-Luc,
1058, rue St-Denis, Montréal, Québec, Canada H2X 3J4
(E-mail: pierre.poitras{at}sympatico.ca).
Received 20 May 1999; accepted in final form 28 August 1999.
 |
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