Glutamate receptors are the primary mediators of excitatory transmission in the central nervous system and are mostly located on the dendrites of postsynaptic neuronal and glial cells, such as astrocytes and oligodendrocytes.
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They bind to the neurotransmitter and amino acid glutamate, and their activity is linked with numerous other neurotransmitter pathways. Glutamate receptors are essential in the mediation of glutamate pathways, which underly many physiological functions, as well as cognitive functions such as learning and memory.
Due to their vital role in these functions, dysfunction of glutamate receptors has been related to disease and injury, and it has been studied closely to develop new therapeutic techniques through exploiting glutamate receptors and the glutamate pathway.
How glutamate receptors work
There are over 20 kinds of glutamate receptors at work in the mammalian central nervous system. They are classified as being either ionotropic (voltage-sensitive), or metabotropic (ligand sensitive). Ionotropic glutamate receptors work quickly and directly generate significant current flows, whereas metabotropic are relatively slow-acting and activate gene expression and protein synthesis to exert their impact.
The differences between the two classes of receptors, and how they work, are discussed below.
When glutamate binds to an ionotropic receptor, it triggers an influx of extracellular sodium and an efflux of potassium ions. These events evoke the depolarization of the postsynaptic membrane, inducing transmission of a signal.
N-methyl D-aspartate (NMDA) is one of the most common types of glutamate ionotropic receptors. NMDA is also permeable to calcium ions, which can have toxic as well as beneficial effects. What’s special about NMDA is that it is a coincidence detector, meaning that glutamate has to bind to the receptor and the post-synaptic cell has to be depolarized for the channel to open, because under normal circumstances magnesium blocks the channel.
There are two other types of ionotropic receptors, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainic acid receptors. While they differ slightly in how they work, their functions are mostly related to learning and memory through plasticity, gene expression, and enhancing glutamate neurotransmission.
These kinds of glutamate receptors, notably NMDA, are found in abundance in the human brain and are considered to be strongly linked with the human capacity for learning and memory, as well as to how the brain recovers following injury.
The slower acting metabotropic glutamate receptors are also related to learning and memory; however, they are also implicated in addiction, motor regulation, and Fragile X syndrome.
These receptors work by overseeing gene expression and protein synthesis, usually resulting in increased excitability of glutamate cells, which influences neurotransmission and consequently impacts on synaptic plasticity that is key to learning and memory.
The process involves glutamate binding with the metabotropic receptor, causing activation of a post-synaptic membrane-bound G-protein, triggering the opening of the membrane channel for signal transmission.
Just like with ionotropic receptors, there are three types of glutamate metabotropic receptors. The first group is mostly expressed in the postsynaptic membrane, and research has linked these receptors specifically to addiction, motor regulation, and Fragile X syndrome, as well as learning and memory.
The second group is also found on post-synaptic cells, as well as on presynaptic cells, and they are thought to play an important role in the suppression of glutamate transmission. Abnormalities with this group of receptors have been associated with mental health problems such as anxiety, schizophrenia, and Alzheimer's disease.
Finally, the third group of metabotropic receptors are also pre-synaptic and thought to inhibit neurotransmitter release. Dysregulation of these receptors has been linked with Parkinson's disease and anxiety disorders.
Role in learning and memory
While the different types of glutamate receptors have slightly different functions, learning and memory are associated with all of them.
Synaptic transmission between neurons and plasticity of these cells is fundamental to allowing learning and memory to take place, and these are the processes that glutamate receptors are known to oversee, making them essential to this human function. More recent evidence has uncovered that the NMDA receptor is most important in learning and memory, mostly because it is vital to the stage of information encoding.
The specific role of AMPARs is still unclear, however, it is theorized that these receptors may be essential to the neuronal excitation that underlies learning processes. Finally, studies have shown that metabotropic glutamate receptors (mGluRs) are fundamental to retrieving and storing information, making them essential to memory processes.
Glutamate receptors and disease
Numerous illnesses have been linked with abnormal functioning of the various glutamate receptors. Fragile X syndrome, Parkinson's disease, anxiety disorders, schizophrenia, Alzheimer's disease, and even addiction have been related to glutamate receptor function.
For example, recent evidence has come to light that has clarified the role of glutamate transmission in schizophrenia. While dopaminergic neurotransmission is already considered a key feature of the illness, new studies are demonstrating that primarily abnormal NMDA and AMPA activity influences schizophrenia, which has led to the exploration of new therapeutic techniques that exploit these receptors functioning.
Also, the characteristic motor symptoms of Parkinson's disease are due to the degeneration of dopaminergic neurons. Ionotropic and metabotropic glutamate receptors have been identified as potential therapeutic targets for triggering a reversal of the effects of altered neurotransmission in Parkinson's disease.
Because glutamate receptors oversee numerous vital functions it is unsurprising that when they fail to function normally, they can give rise to various illnesses. The key aim of research in this field now is to gain a deeper understanding of these relationships to develop more effective treatment strategies.
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