We are studying how glutamate and related ligands interact in the binding site of the NMDA receptor and control its activity.
Glutamate is the major excitatory neurotransmitter in the CNS and activates several classes of receptor - the NMDA receptor (NMDAR) is one of these classes.
NMDARs are implicated in a variety of physiological and pathophysiological processes in the brain, ranging from synapse development, learning and memory to excitotoxic cell death following ischaemic stroke.
Understanding how glutamate and related ligands interact in the binding site of this receptor and control it activity is essential for an understanding of both normal and abnormal function.
By recording the activity of single ion channels, modelling their kinetic behaviour and molecular structure we have published several papers that have furthered our knowledge of this receptor-channel (Chen et al 2004; Wyllie et al 2006).
Recently we have generated a series of chimeric receptor constructs composed of ‘function domains’ from NR2A and NR2D NMDAR subunits and have identified regions within NR2 subunits that influence glycine potency (Chen et al 2008).
We have also shown that voltage-dependent magnesium block is also controlled by regions out with the channel pore itself (Wrighton et al 2008).
The lab is also interested in conducting quantitative pharmacological analysis of agonist and antagonist action at the various NMDAR subtypes (Frizelle et al 2006; Erreger et al 2007)
In related research in the lab we carry out experiments aimed at understanding how calcium entry via NMDAR-dependent and independent routes leads to long-lasting changes in synaptic strength and in particular how ‘local’ translation of mRNA may be involved in the protein synthesis-dependent phase of late-LTP (Vickers et al 2005).
We have provided evidence that postsynaptic modification of synaptic strength that occur via changes in intracellular calcium levels but in an NMDAR-independent manner also involve the same trafficking of AMPA receptors that have been described for conventional plasticity (Baxter & Wyllie 2006).
Combining our interest in NMDAR pharmacology with plasticity we have provided evidence that several studies that have implied specific roles for NMDAR subtypes in different forms of synaptic plasticity may be flawed due to incorrect use of pharmacological antagonists (Frizelle et al 2006).
We gratefully acknowledge present and past support for our research from the following:
Several collaborations exist with other members of the CIP including:
We also have a major collaboration with Dr Steve F Traynelis (Emory University) on structure-function studies of NMDARs.
Perkins EM, Clarkson YL, Sabatier N, Longhurst DM, Millward CP, Jack J, Toraiwa J, Watanabe M, Rothstein JD, Lyndon AR, Wyllie DJA, Dutia MB & Jackson M (2010). Loss of b-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. J Neurosci 30, 4857-4867.
Léveillé F, Papadia S, Fricker M, Soriano FX, Bell KFS, Martel M-A, Puddifoot C, Habel M, Wyllie DJ, Ikonomidou C, Tolkovsky AM & Hardingham GE (2010). Suppression of the intrinsic apoptosis pathway by synaptic activity. J Neurosci 30, 2623-2635.
O’Leary T, van Rossum MCW & Wyllie DJA (2010). Homeostasis of intrinsic excitability in hippocampal neurones: dynamics and mechanism of the response to chronic depolarization. J Physiol 588, 157-170.
Chen PE, Geballe MT, Katz E, Erreger K, Livesey M, O’Toole KK, Le P, Lee CJ, Snyder JP, Traynelis SF & Wyllie DJA (2008). Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes. J Physiol 586, 227-245.
This article was published on Dec 20, 2011