Metabotropic glutamate receptors inhibit mechanosensitivity in vagal sensory neurons.

BACKGROUND AND AIMS: Inhibitory G-protein-coupled receptors have demonstrated potential in treatment of gastroesophageal reflux disease (GERD) through actions on vagal afferent signaling. Metabotropic glutamate receptors (mGluR) belong to this receptor family and have great pharmacologic and molecular diversity, with 8 subtypes. We investigated mGluR in the vagal system of humans and other species. METHODS: Expression of mGluR1-8 in human, dog, ferret, and rodent nodose ganglia was investigated by reverse-transcription polymerase chain reaction. mGluR1-8 immunohistochemistry was performed in combination with retrograde tracing of vagal afferents from ferret proximal stomach to nodose ganglia. Transport of mGluR peripherally was investigated by vagal ligation, followed by immunohistochemistry. Glutamate receptor pharmacology of ferret and rodent gastroesophageal vagal afferents was investigated by testing single fiber responses to graded mechanical stimuli during drug application to their peripheral endings. RESULTS: Messenger RNA for several mGluR was detected in the nodose ganglia of all species. Retrograde tracing indicated that ferret gastric vagal afferents express mGluR protein. Accumulation of immunoreactivity proximal to a ligature showed that mGluR were transported peripherally in the vagus nerves. Glutamate (1-30 mumol/L with kynurenate 0.1 mmol/L) concentration dependently inhibited vagal afferent mechanosensitivity. This was mimicked by selective group II and III mGluR agonists but not by a group I agonist. Conversely, a group III mGluR antagonist increased mechanosensitivity to intense stimuli. CONCLUSIONS: Both exogenous and endogenous glutamate inhibits mechanosensitivity of vagal afferents. Group II (mGluR2 and 3) and group III mGluR (mGluR4, 6, 7, 8) are novel targets for inhibition of vagal signaling with therapeutic potential in, for example, GERD.

Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice.

Mice that lack the winged helix/forkhead gene Foxi1 (also known as Fkh10) are deaf and display shaker/waltzer behavior, an indication of disturbed balance. While Foxi1 is expressed in the entire otic vesicle at E9.5, it becomes gradually restricted to the endolymphatic duct/sac epithelium and at E16.5 Foxi1 expression in the inner ear is confined to this epithelium. Histological sections, paintfill experiments and whole-mount hybridizations reveal no abnormality in inner ear development of Foxi1(-/-) mice before E13.5. Between E13.5 and E16.5 the membranous labyrinth of inner ears from null mutants starts to expand as can be seen in histological sections, paint-fill experiments and three-dimensional reconstruction. Postnatally, inner ears of Foxi1(-/-) mice are extremely expanded, and large irregular cavities, compressing the cerebellum and the otherwise normal middle ear, have replaced the delicate compartments of the wild-type inner ear. This phenotype resembles that of the human sensorineural deafness syndrome Pendred syndrome, caused by mutations in the PDS gene. In situ hybridization of Foxi1(-/-) endolymphatic duct/sac epithelium shows a complete lack of the transcript encoding the chloride/iodide transporter pendrin. Based on this, we would like to suggest that Foxi1 is an upstream regulator of pendrin and that the phenotype seen in Foxi1 null mice is, at least in part, due to defective pendrin-mediated chloride ion resorption in the endolymphatic duct/sac epithelium. We show that this regulation could be mediated by absence of a specific endolymphatic cell type--FORE (forkhead related) cells--expressing Foxi1, Pds, Coch and Jag1. Thus, mutations in FOXI1 could prove to cause a Pendred syndrome-like human deafness.