Neurotoxins are toxins that are destructive to nerve tissue. Neurotoxins are an extensive class of exogenous chemical neurological insults that can adversely affect function in both developing and mature nervous tissue. The term can also be used to classify endogenous compounds, which, when abnormally contacted, can prove neurologically toxic. Though neurotoxins are often neurologically destructive, their ability to specifically target neural components is important in the study of nervous systems. Common examples of neurotoxins include lead, ethanol, glutamate, nitric oxide, botulinum toxin, tetanus toxin, and tetrodotoxin. Some substances such as nitric oxide and glutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations.
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic transmembrane receptor for glutamate (iGluR) and predominantly Na+ ion channel that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core (GluA2 LBD) was the first glutamate receptor ion channel domain to be crystallized.
The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate 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 biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival of otherwise toxic levels of glutamate.
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.
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 algae 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.
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.
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.
Agatoxins are a class of chemically diverse polyamine and peptide toxins which are isolated from the venom of various spiders. Their mechanism of action includes blockade of glutamate-gated ion channels, voltage-gated sodium channels, or voltage-dependent calcium channels. Agatoxin is named after the funnel web spider which produces a venom containing several agatoxins. There are different agatoxins. The ω-agatoxins are approximately 100 amino acids in length and are antagonists of voltage-sensitive calcium channels and also block the release of neurotransmitters. For instance, the ω-agatoxin 1A is a selective blocker and will block L-type calcium channels whereas the ω-agatoxin 4B will inhibit voltage sensitive P-type calcium channels. The μ-agatoxins only act on insect voltage-gated sodium channels.
Philanthotoxins are components of the venom of the Egyptian solitary wasp Philanthus triangulum, commonly known as the European beewolf. Philanthotoxins are polyamine toxins, a group of toxins isolated from the venom of wasps and spiders which immediately but reversibly paralyze their prey. δ-philanthotoxin, also known as PhTX-433, is the most active philanthotoxin that can be refined from the venom. PhTX-433 functions by non-selectively blocking excitatory neurotransmitter ion channels, including nicotinic acetylcholine receptors (nAChRs) and ionotropic glutamate receptors (iGluRs). Synthetic analogues, including PhTX-343 and PhTX-12, have been developed to improve selectivity. While the IC50 values of philanthotoxins varies between analogues and receptor subunit composition, the IC50 value of PhTX-433 at the iGluR AMPA receptor naturally expressed in locust leg muscle is 18 μM and the IC50 value at rat nAChRs is 1 μM.
Delucemine (NPS-1506) is a drug which acts as an NMDA antagonist and a serotonin reuptake inhibitor, and has neuroprotective effects. It was originally investigated for the treatment of stroke and in 2004 was studied as a potential antidepressant.
Pompilidotoxins (PMTXs) are toxic substances that can only be found in the venom of several solitary wasps. This kind of wasp uses their venom to offensively capture prey and is relatively harmless to humans. This is in stark contrast to social insects that defend themselves and their colonies with their venom.
Joro spider toxin – a toxin which was originally extracted from the venom of the joro spider, originally native to Japan.
Hanatoxin is a toxin found in the venom of the Grammostola spatulata tarantula. The toxin is mostly known for inhibiting the activation of voltage-gated potassium channels, most specifically Kv4.2 and Kv2.1, by raising its activation threshold.
Agelenin, also called U1-agatoxin-Aop1a, is an antagonist of the presynaptic P-type calcium channel in insects. This neurotoxic peptide consists of 35 amino acids and can be isolated from the venom of the spider Allagelena opulenta.
Kaitocephalin is a non-selective ionotropic glutamate receptor antagonist, meaning it blocks the action of the neurotransmitter glutamate. It is produced by the fungus Eupenicillium shearii. Although similar molecules have been produced synthetically, kaitocephalin is the only known naturally occurring glutamate receptor antagonist. There is some evidence that kaitocephalin can protect the brain and central nervous system, so it is said to have neuroprotective properties. Kaitocephalin protects neurons by inhibiting excitotoxicity, a mechanism which causes cell death by overloading neurons with glutamate. Because of this, it is of interest as a potential scaffold for drug development. Drugs based on kaitocephalin may be useful in treating neurological conditions, including Alzheimer's, amyotrophic lateral sclerosis (ALS), and stroke.
Protoxin-I, also known as ProTx-I, or Beta/omega-theraphotoxin-Tp1a, is a 35-amino-acid peptide neurotoxin extracted from the venom of the tarantula Thrixopelma pruriens. Protoxin-I belongs to the inhibitory cystine knot (ICK) family of peptide toxins, which have been known to potently inhibit voltage-gated ion channels. Protoxin-I selectively blocks low voltage threshold T-type calcium channels, voltage gated sodium channels and the nociceptor cation channel TRPA1. Due to its unique ability to bind to TRPA1, Protoxin-I has been implicated as a valuable pharmacological reagent with potential applications in clinical contexts with regards to pain and inflammation
Delta hexatoxin Hv1 is a neurotoxic component found in the venom of the Australian funnel web spider.
