N-Methyl-d-aspartic acid or N-Methyl-d-aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors. NMDA receptors are particularly important when they become overactive during, for example, withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.
The N-methyl-D-aspartatereceptor, is a glutamate receptor and ion channel protein found in nerve cells. The NMDA receptor is one of three types of ionotropic glutamate receptors. The other receptors are the AMPA and kainate receptors. It is activated when glutamate and glycine bind to it, and when activated it allows positively charged ions to flow through the cell membrane. The NMDA receptor is very important for controlling synaptic plasticity and memory function.
In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.
An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travel, each neuron often making numerous connections with other cells. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.
In excitotoxicity nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or N-methyl-D-aspartic acid (NMDA) become pathologically high resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter glutamate significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biologic life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival to otherwise toxic levels of glutamate.
Dizocilpine (INN), also known as MK-801, is a noncompetitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is normally blocked with a magnesium ion and requires depolarization of the neuron to remove the magnesium and allow the glutamate to open the channel, causing an influx of calcium, which then leads to subsequent depolarization. Dizocilpine binds inside the ion channel of the receptor at several of PCP's binding sites thus preventing the flow of ions, including calcium (Ca2+), through the channel. Dizocilpine blocks NMDA receptors in a use- and voltage-dependent manner, since the channel must open for the drug to bind inside it. The drug acts as a potent anti-convulsant and probably has dissociative anesthetic properties, but it is not used clinically for this purpose because of the discovery of brain lesions, called Olney's lesions (see below), in laboratory rats. Dizocilpine is also associated with a number of negative side effects, including cognitive disruption and psychotic-spectrum reactions. It inhibits the induction of long term potentiation and has been found to impair the acquisition of difficult, but not easy, learning tasks in rats and primates. Because of these effects of dizocilpine, the NMDA receptor pore-blocker ketamine is used instead as a dissociative anesthetic in human medical procedures. While ketamine may also trigger temporary psychosis in certain individuals, its short half-life and lower potency make it a much safer clinical option. However, dizocilpine is the most frequently used non-competitive NMDA receptor antagonist in animal models to mimic psychosis for experimental purposes.
AP-7 is a selective NMDA receptor (NMDAR) antagonist that competitively inhibits the glutamate binding site and thus activation of NMDAR. It has anticonvulsant effects.
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.
Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.
The induction of NMDA receptor-dependent long-term potentiation (LTP) in chemical synapses in the brain occurs via a fairly straightforward mechanism. A substantial and rapid rise in calcium ion concentration inside the postsynaptic cell is most possibly all that is required to induce LTP. But the mechanism of calcium delivery to the postsynaptic cell in inducing LTP is more complicated.
Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the red alga Digenea simplex. They have been traditionally classified as a non-NMDA-type receptor, along with the AMPA receptor. KARs are less understood than AMPA and NMDA receptors, the other ionotropic glutamate receptors. Postsynaptic kainate receptors are involved in excitatory neurotransmission. Presynaptic kainate receptors have been implicated in inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.
The ischemic (ischaemic) cascade is a series of biochemical reactions that are initiated in the brain and other aerobic tissues after seconds to minutes of ischemia. This is typically secondary to stroke, injury, or cardiac arrest due to heart attack. Most ischemic neurons that die do so due to the activation of chemicals produced during and after ischemia. The ischemic cascade usually goes on for two to three hours but can last for days, even after normal blood flow returns.
Quisqualic acid is an agonist of the AMPA, kainate, and group I metabotropic glutamate receptors. It is one of the most potent AMPA receptor agonists known. It causes excitotoxicity and is used in neuroscience to selectively destroy neurons in the brain or spinal cord. Quisqualic acid occurs naturally in the seeds of Quisqualis species. Research conducted by the USDA Agricultural Research Service, has demonstrated quisqualic acid is also present within the flower petals of zonal geranium and is responsible for causing rigid paralysis of the Japanese beetle. Quisqualic acid is thought to mimic L-glutamic acid, which is a neurotransmitter in the insect neuromuscular junction and mammalian central nervous system.
Stuart Graham Cull-Candy is a British neuroscientist. He holds the Gaddum Chair of Pharmacology and a personal Chair in Neuroscience at University College London. He is also a member of the Faculty of 1000 and holds a Royal Society - Wolfson Research position.
A channel modulator, or ion channel modulator, is a type of drug which modulates ion channels. They include channel blockers and channel openers.
In neuroscience, glutamate refers to the anion of glutamic acid in its role as a neurotransmitter: a chemical that nerve cells use to send signals to other cells. It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.
Mark Andrew Lemmon an English-born biochemist, is a professor of Pharmacology at Yale University where he co-directs the Cancer Biology Institute with Joseph Schlessinger.
David Lodge FRS is a research fellow in the Department of Physiology and Pharmacology at the University of Bristol.
Stephen F. Heinemann (1939–2014) was a professor of neuroscience at the Salk Institute. He was an early researcher in the field of molecular neuroscience, contributing to the current knowledge of how nerves communicate with each other, and the role of neurotransmitters. Stephen Heinemann died August 6, 2014 of kidney failure.
