Ionotropic Glutamate Receptors
The broad objective of our research is to develop a detailed understanding of the molecular determinants of the properties of efficacy, affinity and desensitisation at ionotropic glutamate receptors (iGluRs) of the AMPA/kainate class.
iGluRs – their important role in the central nervous system
Binding of (S)-glutamate to iGluRs is a key step in the mechanism of rapid excitatory synaptic transmission among nerve cells (neurons) within the mammalian central nervous system (CNS). iGluRs are important in the development and function of the CNS and are implicated in learning and memory formation. Furthermore, iGluRs seem to be associated with certain neurological and psychiatric diseases (e.g. stroke, epilepsy, depression, stress, ischemia-related brain damage, trauma, sustained-seizure damage, Huntington's disease, ALS, Parkinsonism-dementia-like syndrome, Alzheimer's disease) and are therefore considered as potential drug targets.
iGluRs – their structure and function
iGluRs are tetrameric, ligand-gated ion channels and have been divided into three different classes on the basis of protein sequence identity and ligand selectivity: AMPA, kainic acid (KA) and NMDA receptors.
iGluRs couple the energy of agonist binding to the opening of a transmembrane ion pore, allowing influx of Na+, K+ or Ca2+ ions.
This causes membrane depolarisation and neuronal excitation, producing an electrical signal from the chemical stimulus (i.e. glutamate) which activates the neuron to produce a response.
The type of response produced depends upon the specific types of iGluRs and neurons being activated and upon the specific brain region in which they are located.
It has been shown by us and many others that two regions, D1 and D2, of the receptor protein contain the glutamate-binding core of the receptors. We have further verified that this core is necessary and sufficient to achieve binding properties similar to those of the intact membrane-bound receptor.
Pharmacological studies of the recombinant iGluRs have complemented the biostructural studies, allowing construction of reliable, computer-generated homology models of the iGluR binding domains and a quantitative structure-activity relationship (QSAR) model for ligand binding, selectivity and channel activation.
In addition to in vitro pharmacological studies of iGluRs, we are conducting in vivo pharmacological investigations of selected iGluR ligands in rodent models of cognition, pain, anxiety, stress, depression and brain injury.