Chronic exposure to ammonia alters basal and NMDA-induced phosphorylation of NMDA receptor-subunit NR1

Hyperammonemia is responsible for many of the neurological alterations in patients with hepatic encephalopathy by mechanisms that remain unclear. Hyperammonemia alters phosphorylation of brain protein kinase C substrates and impairs N-methyl-d-aspartate (NMDA) receptor-associated signal transduction. The aim of this work was to analyze, in rat cerebellar neurons in culture, the effects of ammonia exposure on NMDA receptor phosphorylation, MK801 binding and surface expression. Ammonia reduces MK801 binding to NMDA receptors and the surface expression of the NR1 and NR2A subunits. As phosphorylation of serines in the NR1 C1 cassette has been implied in receptor trafficking, we assessed whether hyperammonemia alters phosphorylation of these serines. Basal phosphorylation of serines 890, 896 and 897 was increased in neurons exposed to ammonia, while NMDA-induced phosphorylation of S896 and S897 was reduced. Exposure to ammonia also increased basal phosphorylation of Akt but reduced NMDA and BDNF stimulation of Akt phosphorylation. These results suggest that alterations in receptor surface expression and possibly the phosphorylation state of the NR1 subunit of NMDA receptors may contribute to the impairment by ammonia of signal transduction pathways modulated by NMDA receptors.