Effects of Glutamate on Glycerophospholipid Synthesis

In cortical cultures, AMPA receptor activation is also linked to chohne release and inhibition of PtdCho synthesis (Gasull et al., 2001). In contrast, the selective stimulation of KA receptors has no affect on the release of choline and does not reduce PtdCho synthesis. Sensitization of AMPA receptors plays an important role during this process. Thus in the presence of cyclothiazide (CTZ), an inhibitor of AMPA receptor desensitization (Bertolino et al., 1993), AMPA receptor over stimulation becomes neurotoxic after 24 h of treatment. However, significant neuronal death does not occur until the first hour of treatment. In contrast, stimulation of non-sensitized AMPA receptors causes a marked inhibition of PtdCho synthesis within 5 min of treatment. These observations suggest that AMPA-mediated inhibition of PtdCho synthesis precedes membrane permeability changes that may cause excitotoxic necrotic neuronal cell death (Gasull et al., 2001). 

It is postulated that inhibition of PtdCho synthesis and the release of choline are key steps associated with excitotoxicity and are common to NMDA and AMPA receptor stimulation. The mechanism of inhibition of PtdCho is not fully understood. Metabolic labeling experiments in cortical cultures demonstrate that NMDA receptor over activation does not modify the activity of phosphochohne or phospho-ethanolamine cytidylyltransferases but strongly inhibits choline and ethanolamine phosphotransferase activities. This effect is observed well before any significant membrane damage and cell death. Moreover, cholinephosphotransferase activity is lower in microsomes from NMDA-treated cells. These results show that membrane 

5 Excitatory Amino Acid Receptors and Neural Membrane 

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