Glutamate is the main excitatory neurotransmitter in the central nervous system. It activates specific membrane proteins known as glutamate receptors. Our studies focus on ionotropic glutamate receptors, which, when activated, allow ions to flow across the cell membrane.
Glutamate is the main excitatory neurotransmitter in the central nervous system. It activates specific membrane proteins known as glutamate receptors. Our studies focus on ionotropic glutamate receptors, which, when activated, allow ions to flow across the cell membrane. The membrane current leads to fast changes in the membrane potential (excitation) and to the spread of information to other neurons. Ionotropic glutamate receptors participate in all neuronal circuits and are thus involved in virtually every function of the nervous system. These receptors mediate changes in synaptic strength, which underlie the formation and storage of memory traces in the brain.
There are three known families of ionotropic glutamate receptors (NMDA, AMPA and kainate receptors), similar in their structure, but different in their kinetic properties, sensitivity to different pharmacological agents and membrane distribution. A functional NMDA receptor consists of four GluN subunits. NMDA receptor subunits are coded by 7 GRIN genes, with the GluN1 subunit existing in 8 splice variants.There is much clinical and experimental evidence that despite their essential role in normal physiology, ionotropic glutamate receptors can, under certain pathological conditions, participate in the development of serious psychiatric and neurological disorders. For example, excessive activation of NMDA receptors leads to neuronal death known as excitotoxicty. Excitotoxicity causes brain damage resulting from brain ischemia, perinatal hypoxia, asphyxia, cardiac arrest, and brain trauma. Excitotoxicity is also thought to participate in the loss of neurons and cognitive damage associated with Alzheimer's disease and Parkinson's disease.
Further, de-novo nonsynonymous mutations (missense or nonsense), frame shifts, or splice site mutations in GRIN genes that encode for NMDA receptor subunits were identified in individuals with defined neurodevelopmental and psychiatric disorders such as intellectual disability, developmental delay, autism spectrum disorder, epileptic encephalopathy, schizophrenia, and to a lesser extent, attention deficit hyperactivity disorder, cerebral visual impairment, and Alzheimer’s disease.
Simulation of conformational changes of the NMDA receptor induced by glutamate binding.
We use advanced electrophysiology methods, primarily the patch-clamp technique, to study ligand-gated ion channel activity at the level of whole cells, synapses, or even single channels. For complex understanding of ion channel properties, we combine electrophysiology with quantitative analytical techniques, molecular biology, biochemistry, immunohistochemistry, microfluorometrics, optogenetics, and computational methods (molecular dynamics simulations).