Journal
NEUROGASTROENTEROLOGY AND MOTILITY
Volume 23, Issue 2, Pages e91-e103Publisher
WILEY
DOI: 10.1111/j.1365-2982.2010.01644.x
Keywords
glutamate; guinea pig ileum; in vitro ischemia; reperfusion; myenteric plexus; N-methyl-d-aspartate receptors
Funding
- Italian Ministry of University and Research
- Universities of Insubria
- Universities of Pavia
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Background Ischemic episodes lead to profound functional and structural alterations of the gastrointestinal tract which may contribute to disorders of intestinal motility. Enhancement of glutamate overflow and the consequent activation of NMDA (N-methyl-d-aspartate) receptors may participate to such changes by modulating different enteric neurotransmitter systems, including cholinergic motor pathways. Methods The molecular mechanism/s underlying activation of NMDA receptors in the guinea pig ileum were investigated after glucose/oxygen deprivation (in vitro ischemia) and during reperfusion. Key Results The number of ileal myenteric neurons positive for NR1, the functional subunit of NMDA receptors, and its mRNA levels were unchanged after in vitro ischemia/reperfusion. In these conditions, the protein levels of NR1, and of its phosphorylated form by protein kinase C (PKC), significantly increased in myenteric neurons, whereas, the levels of NR1 phosphorylated by protein kinase A (PKA) did not change, with respect to control values. Spontaneous glutamate overflow increased during in vitro ischemia/reperfusion. In these conditions, the NMDA receptor antagonists, d(-)-2-amino-5-phosphonopentanoic acid [(d)-AP5] (10 mu mol L-1) and 5,7-dichlorokynurenic acid (5,7-diClKyn acid) (10 mu mol L-1) and the PKC antagonist, chelerythrine (1 mu mol L-1), but not the PKA antagonist, H-89 (1 mu mol L-1), were able to significantly depress the increased glutamate efflux. Conclusions & Inferences The present data suggest that in the guinea pig ileum during in vitro ischemia/reperfusion, NR1 protein levels increase. Such event may rely upon posttranscriptional events involving NR1 phosphorylation by PKC. Increased NR1 levels may, at least in part, explain the ability of NMDA receptors to modulate a positive feedback on ischemia/reperfusion-induced glutamate overflow.
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