Role of Glutamate Channels in Epilepsy
Temporal lobe epilepsy, the most common form of adult focal epilepsies, is often resistant to anticonvulsant therapy. Spontaneous seizures are thought to occur when the inherent balance between excitation and inhibition is disturbed. Glutamate is the chief excitatory neurotransmitter in the brain. One type of glutamate receptor, the N-methyl D-aspartate receptor (NMDA) has been reported to be increased after some types of seizure induction. We are elucidating the role of NMDA receptors in increasing overall excitation in the hippocampus in epilepsy models by probing the electrical signals in individual nerve cells in response to electrical stimuli. We hope we can use this model to one day evaluate drugs which will prevent spontaneous seizures.
Glutamate Receptor Activation & Desensitization
Although the ligand binding pockets of glutamate receptors have been crystallized, basic insight into the conformational changes that take place when these ligand gated channels open and desensitize is still unknown. We analyze electrophysiological voltage clamp experiments with specific mathematical models to determine the molecular transitions required in the processes that open and modulate channels.
Are Scorpion Toxins the Drug of the Future?
Some types of chronic pain and seizures stem from over-activity of one type of channel in nerve cells called sodium channels. Even among sodium channels, there are several different subtypes, of which only one or two may be involved in these chronic disease states. Scorpion toxins are small proteins that can be highly selective for specific sodium channel subtypes. They can differentiate between mammals and insects as well as between sodium channels in different tissues such as the brain, heart or muscle. Furthermore, these toxins have also been mutated to change their modulatory action and their specificity. In this way, we hope that we can determine what parts of these small proteins govern their specificity and their action. With such an understanding, we may be able to produce new drugs to alleviate chronic pain or prevent chronic spontaneous seizures common to some forms of epilepsy.
Research Key Words: Epilepsy, Electrophysiology, Glutamate, Ion Channels