Assembly and targeting of NMDA receptors
Prof A. Stephenson
Information in our brains is processed by a network of nerve cells. Nerve cells or neurons have an asymmetric structure. An important region of a neuron is the synaptic area which is where the communication between the adjacent neurons occurs. One important component of the synapse is the neurotransmitter receptor protein which is integral in receiving the message from one neuron and then transducing this into a response in the recipient nerve cell. The receptor proteins are made in the cell nucleus which is often very distant from the synapse thus accessory proteins are required to traffic the receptors to their correct location within the neuron. This is requisite for proper neuronal function. The focus of this project is to characterise the assembly of an important family of excitatory neurotransmitter receptors, the NMDA receptors, and their associated scaffolding proteins. NMDA receptors are complex, multi-subunit proteins.
A schematic diagram depicting pertinent features of NMDA neurotransmitter receptors
There are several forms of NMDA receptor. Each has its own pharmacological profile, a particular subcellular distribution and its own developmental profile; these properties contribute to the different functions of NMDA receptor subtypes in the adult brain and during the development of the central nervous system. In this proposal we aim to determine the factors that are requisite for the association of the appropriate NMDA receptor subunits and their efficient trafficking to the cell surface. We will examine the role of cysteine residues, the integrity of ligand binding and channel domains and the recently discovered HLFA endoplasmic reticulum export sequence in the assembly, maturation and cell surface expression of NMDA receptor subtypes.
A schematic diagram showing the organization of the post--synaptic NMDA receptor macromolecular signalling complex.
We will further study the roles of the two splice variants of PSD-95 in the potential differential targeting within neurones and finally, in a collaborative project with a group in France, study the activity-dependent movement of NMDA receptors at synapses. These studies will yield fundamental knowledge on the regulation of excitatory neurotransmitter transmission in the mammalian brain.
Figures are from Stephenson, F.A., Cousins, S.L. and Kenny, A.V. (2008) Molecular Membrane Biology 25, 311-320. Assembly and forward trafficking of NMDA receptors.
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