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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. 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. 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 μmol L(-1)) and 5,7-dichlorokynurenic acid (5,7-diClKyn acid) (10 μmol L(-1)) and the PKC antagonist, chelerythrine (1 μmol L(-1)), but not the PKA antagonist, H-89 (1 μmol L(-1)), were able to significantly depress the increased glutamate efflux. 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. © 2010 Blackwell Publishing Ltd.


C Giaroni, E Zanetti, D Giuliani, R Oldrini, S Marchet, E Moro, P Borroni, M Trinchera, F Crema, S Lecchini, G Frigo. Protein kinase C modulates NMDA receptors in the myenteric plexus of the guinea pig ileum during in vitro ischemia and reperfusion. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society. 2011 Feb;23(2):e91-103

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PMID: 21159064

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