Pathogenesis and therapy for idiopathic dyspepsia. 2006
Drugs for treatment of costipation
Receptor for motilin identified in the human gastrointestinal system.
Figure 4. Expression of MTL-R1A in the human GI tract by in situ hybridization and colocalization with nitric acid synthase-containing neurons: (A) colon, antisense probe for MTL-R1A; (B) colon, control sense probe for MTL-R1A; © colon, double-labeling to detect MTL-R1A (antisense probe) and NOS with antibody to NOS; (D) jejunum, antisense probe for MTL-R1A; and (E and F) duodenum, antisense probe for MTL-R1A. In situ signal is seen in red (Texas Red), NOS immunoreactivity in green (FITC), and all cell nuclei in blue (DAPI). All scale bars are 15 µm.
Feighner SD, Tan CP, McKee KK, Palyha OC, Hreniuk DL, Pong SS, Austin CP, Figueroa D, MacNeil D, Cascieri MA, Nargund R, Bakshi R, Abramovitz M, Stocco R, Kargman S, O'Neill G, Van Der Ploeg LH, Evans J, Patchett AA, Smith RG, Howard AD.
Department of Metabolic Disorders, Department of Medicinal Chemistry, Merck Research Laboratories, Building RY-80Y-265, 126 East Lincoln Avenue, Rahway, NJ 07065, USA.
Motilin is a 22-amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract of humans and other species. It affects gastric motility by stimulating interdigestive antrum and duodenal contractions. A heterotrimeric guanosine triphosphate-binding protein (G protein)-coupled receptor for motilin was isolated from human stomach, and its amino acid sequence was found to be 52 percent identical to the human receptor for growth hormone secretagogues. The macrolide antibiotic erythromycin also interacted with the cloned motilin receptor, providing a molecular basis for its effects on the human GI tract. The motilin receptor is expressed in enteric neurons of the human duodenum and colon. Development of motilin receptor agonists and antagonists may be useful in the treatment of multiple disorders of GI motility.
Role of G.proteins
J Virol. 1998
Dissemination of lymphocytic choriomeningitis virus from the gastric mucosa requires G protein-coupled signaling.
Yin C, Djavani M, Schenkel AR, Schmidt DS, Pauza CD, Salvato MS.
Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
The gastric mucosa is an important portal of entry for lymphocytic choriomeningitis virus (LCMV) infections. Within hours after intragastric (i.g.) inoculation, virus appears in the gastric epithelia, then in the mesenteric lymph nodes and spleen, and then in the liver and brain. By 72 h i.g.-inoculated virus is widely disseminated and equivalent to intravenous (i.v.) infection (S. K. Rai, B. K. Micales, M. S. Wu, D. S. Cheung, T. D. Pugh, G. E. Lyons, and M. S. Salvato. Am. J. Pathol. 151:633-639, 1997). Pretreatment of mice with a G protein inhibitor, pertussis toxin (PTx), delays LCMV dissemination after i.g., but not after i.v., inoculation. Delayed infection was confirmed by plaque assays, by reverse transcription-PCR, and by in situ hybridization. The differential PTx effect on i.v. and i.g. infections indicates that dissemination from the gastric mucosa requires signals transduced through heterotrimeric G protein complexes. PTx has no direct effect on LCMV replication, but it modulates integrin expression in part by blocking chemokine signals. LCMV infection of macrophages up-regulates CD11a, and PTx treatment counteracts this. PTx may prevent early LCMV dissemination by inhibiting the G protein-coupled chemotactic response of macrophages infected during the initial exposure, thus blocking systemic virus spread.
Altered responses to gastroduodenal acid exposure
have also been identified as pathophysiologic mechanisms
in FD.7 Gastric acid secretion is similar in patients
with FD and healthy controls.89 However, there is evidence
of a beneficial effect of acid-suppressive drugs in
a proportion of FD patients.
Holzer et al.90 showed that intragastric administration
of a small volume of hydrochloric acid altered gastric
motor activity and gastric emptying via a complex
array of extrinsic nerve reflexes in phenobarbitalanesthetized
rats. It is possible that the gastropyloric
motor changes induced by luminal acid challenge have a
bearing on the motor disturbances underlying FD.
It has been demonstrated that duodenal infusion of
hydrochloric acid induces nausea and that the duodenal
motor response to acid is decreased in FD patients.91
Lee et al.92 reported that duodenal acidification induces
proximal gastric relaxation, increases sensitivity to gastric
distension, and inhibits gastric accommodation to a
meal. In addition, they found that spontaneous duodenal
acid exposure was increased in a subset (64%) of FD
patients with prominent nausea, and that this condition
was associated with more severe dyspeptic symptoms.93
Thus, the potential role of acid in the pathogenesis of
FD may be based on increased duodenal acid exposure,
decreased duodenal clearance of acid, hypersensitivity
to acid, and/or the development of acid-mediated GI
motor abnormalities. Schwartz et al.94 confirmed that
alterations in sensorimotor responses to intraduodenal
acid and nutrients are chemospecific, suggesting an abnormality
at the level of visceral afferents or mucosal
chemoreceptors in FD patients. However, a direct relationship
between duodenal acid exposure and symptom
severity is lacking, and duodenal responses to exogenous
acid were unaffected by 5-hydroxytryptamine-3
(5-HT3) receptor antagonism.93
Antidopaminergic GI prokinetics have been exploited
clinically for the management of FD. The
prokinetic effect of these drugs is mediated through the
blockade of enteric (neuronal and muscular) inhibitory
dopamine-2 (D2) receptors. Their pharmacological profiles
differ in terms of their molecular structure, affinity
for D2 receptors, interaction with other receptor systems,
and ability to permeate the blood–brain barrier.116
The benzamide derivate levosulpiride is a D2 antagonist
that can accelerate gastric emptying and decrease the
perception of gastric distension with an action unrelated
to change of gastric tone.117 Mearin et al.118 compared
the clinical efficacy of levosulpiride and cisapride, a 5-
HT4 agonist/weak 5-HT3
Recent insights into digestive motility in functional dyspepsia 2006