Expression of a functional metabotropic glutamate receptor 5 on enteric glia is altered in states of inflammation

Abstract

The metabotropic glutamate receptor 5 (mGluR5) is expressed by astrocytes and its expression is modulated by inflammation. Enteric glia have many similarities to astrocytes and are the most numerous cell in the enteric nervous system (ENS). We investigated whether enteric glia express a functional mGluR5 and whether expression of this receptor was altered in colitis. In both enteric plexuses of the ileum and colon of guinea pigs and mice, we observed widespread glial mGluR5 expression. Incubation of isolated segments of the guinea pig ileum with the mGluR5 specific agonist RS-2-chloro-5-hydroxyphenylglycine (CHPG) caused a dose-dependent increase in the glial expression of c-Fos and the phosphorylated form of the extracellular signal-regulated kinase 1/2. Preincubation of tissues with the group I metabotropic glutamate receptor antagonist, S-4-carboxyphenylglycine, abolished the effects of CHPG. We examined mGluR5 expression in the guinea pig trinitrobenzene sulfonic acid and the IL-10 gene-deficient (IL-10(-/-)) mouse models of colitis. In guinea pigs, mGluR5 immunoreactivity became diffusely localized over the colonic myenteric ganglia, suggesting a change in receptor distribution. In contrast, glial mGluR5 expression was significantly reduced in the colonic myenteric plexus of IL-10(-/-) mice, as assessed with both real-time quantitative RT-PCR as well as immunohistochemistry and image analysis. These changes occurred without concomitant changes to enteric ganglia or glial fibrillary acidic protein expression in the IL-10(-/-) mouse. Our data suggest that enteric glia are a functional target of the glutamatergic neurotransmitter system in the ENS and that changes in mGluR5 expression may be of physiological significance during colitis.

Enteric Glia Are Targets of the Sympathetic Innervation of the Myenteric Plexus in the Guinea Pig Distal Colon

“…Much like in CNS astrocytes, propagating calcium waves have been reported in cultured enteric glia in response to mechanical stimulation (Zhang et al, 2003). Furthermore, guinea pig enteric glia express mGluR5 receptors, raising the possibility that they may respond to glutamate (Nasser et al, 2007). There are, however, several observations that argue against this scenario in our preparations.…”

“…Immunohistochemistry was performed as described by Nasser et al (2007). Briefly, LMMP whole mounts were prepared from Zamboni's fixed tissue, and primary antibodies to TH (rabbit anti-TH, 1:1000; Eugene Biotech) and protein gene product 9.5 (PGP) (mouse anti-PGP, 1:500; Ultraclone) were applied for 48 h at 4°C.…”

Exciting Times beyond the Brain: Metabotropic Glutamate Receptors in Peripheral and Non-Neural Tissues

“…However, conflicting evidence also shows that the mGlu5 receptor antagonist MPEP, as well as (S)-4-carboxyphenylglycine, is able to depress slow EPSPs in submucosal neurons (Liu and Kirchgessner, 2000). It is noteworthy that another piece of work shows that expression of functional mGlu5 receptors in ileum and colon of guinea pig, rat, and mouse is restricted to enteric glia (Nasser et al, 2007). Glial c-fos immunoreactivity and phosphorylated ERK1/2 levels are increased upon mGlu5 activation in guinea pigs, and chemically induced colitis was associated with redistribution of the receptor.…”

“…Glial c-fos immunoreactivity and phosphorylated ERK1/2 levels are increased upon mGlu5 activation in guinea pigs, and chemically induced colitis was associated with redistribution of the receptor. On the other hand, a mouse model of colitis (the IL-10 gene-deficient mouse, characterized by spontaneous chronic intestinal inflammation) shows significantly lower levels of glial mGlu5 receptor expression in colon myenteric plexus (Nasser et al, 2007).…”

Metabotropic Glutamate Receptors in Peripheral Tissues: Implications for Toxicology

“…mGluR1/5 signaling may increase intracellular pH in the duodenum (Akiba et al, 2009). The presence of mGluR2/3 and mGluR1/5 has been demonstrated in neurons of jejunum and ileum, suggesting that they may play a role in the regulation of intestinal motility (Larzabal et al, 1999;Liu & Kirchgessner, 2000;Nasser et al, 2007). On the other hand, mGluR4 and mGluR7 are expressed in colon mucosa (Chang et al, 2005;Julio-Peper et al, 2010).…”