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Investigation of the functional propreties of NMDA receptors containing more than one type of NR2 subunit and the functional stoichiometry of the high-affinity Zn² binding site.


NMDA receptors (Nadirs) are implicated in many neuropsychological and neuropath logical processes including schema, epilepsy and schizophrenia. They are heteromeric gated-gated ion channels likely composed of two NR1 and two NR2 subunits. Extra cellular agents including Zn. Co-released at some synapses with glutamate modulate nadirs, Zn is a potentially important physiological regulator of Malfunction. The NR2 subunit subtype, NR2A being the most sensitive, determines Zn affinity for Nadirs. InNR2A the high-affinity Zn binding site maps to the N-terminal domain, whilst in NR2B the homologous domain binds the neuroprotectant ifenprodil, a non-competitive antagonist specific for NR2B-containing NMDARs. Demodulator N-terminal domains therefore present potentially interesting pharmaceutical targets. To date, functional studies on recombinant Nadirs have centred on receptors containing only one NR2 subunit subtype, however, biochemical evidence suggests that many native Nadirs contain two subtypes of NR2.Using mutated receptors we will isolate populations of recombinant "triplet" receptors containing two different subtypes of NR2. Their function will be assessed using electrophysiological techniques, allowing us to answer several key questions. Firstly, "triplets" containing a wild-type NR2A subunit and a NR2A subunit lacking the functional high-affinity Zn binding site will be used to determine the functional stoichiometry of the Zn inhibition. Secondly, using "triplets" containing both a NR2A and a NR2B, NR2C or NR2D subunit, we will assess the functional properties of recombinant Nadirs containing two types of NR2 subunit. Of particular interest is the interaction in NR2A/NR2B "triplets" between Zn and ifenprodil. Finally, to assess the physiological relevance of” triplet" Nadirs, we will compare the properties of recombinant "triplets" and native receptors found in brain regions where more than one type of#

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Funding Scheme

EIF - Marie Curie actions-Intra-European Fellowships


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