Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.653384
Title: Engineering mutations into the mouse NR2B gene of the NMDA receptor
Author: Kicsi, E. G.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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Abstract:
N-methyl-D-aspartate (NMDA) receptors are glutamate gated ion channels and essential for forms of synaptic plasticity, learning and memory formation. The developmental expression patterns of NMDA receptor subunits suggest that they are important in early postnatal life and therefore it is not surprising that mice lacking NR1 and NR2B subunits die shortly after birth. The C-terminal domain of NR2B subunits is not necessary for channel function, but binds proteins involved in signal transduction. Since mice expressing the C-terminal truncated form of the NR2B subunit also die at birth, this suggests the importance of the C-terminal domain in the signalling pathways. The C-terminus of the NR2B subunit is 616 in length and the terminal valine residue is essential for binding the PDZ domains of postsynaptic density protein-95 (PSD-95). PSD-95 is essential for plasticity and learning and is an adaptor for other signalling proteins such as synaptic Ras GTPase (SynGAP) and neuronal nitric oxidase synthase (nNOS). Knockin mice were created, which lack the terminal valine residue of NR2B in order to disrupt the connection between the NR2B and the downstream signalling components. Although much is needed to be done to properly characterise this mutant, we made a very important step forward to understand how molecular interactions within the C-terminal domain of the NR2B subunit affect the function of the NMDA receptor by generating viable mutants. I also created a mutation in the calcium- and calmodulin-dependent protein kinase II (CaMKII) binding site of NR2B, which eliminates a different signalling pathway, and finally, deleted the COOH-exon of the NR2B subunit and replaced it by that of the NR2A, which experiment shows the importance of the interactions via the NR2B cytoplasmic tail.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.653384  DOI: Not available
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