Postsynaptic
density

Voltage-
gated Ca⁺⁺
channel

Synaptic
vesicle

Neurotransmitter
transporter

Receptor

Neurotransmitter

Axon terminal

Synaptic cleft

Dendrite

Structure of a typical chemical synapse

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.^[1]

Neurotransmitters are released from synaptic vesicles into the synaptic cleft where they are able to interact with neurotransmitter receptors on the target cell. The neurotransmitter's effect on the target cell is determined by the receptor it binds to. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are readily available and often require a small number of biosynthetic steps for conversion.

Neurotransmitters are essential to the function of complex neural systems. The exact number of unique neurotransmitters in humans is unknown, but more than 100 have been identified.^[2] Common neurotransmitters include glutamate, GABA, acetylcholine, glycine and norepinephrine.

Mechanism and cycle

Synthesis

Neurotransmitters are generally synthesized in neurons and are made up of, or derived from, precursor molecules that are found abundantly in the cell. Classes of neurotransmitters include amino acids, monoamines, and peptides. Monoamines are synthesized by altering a single amino acid. For example, the precursor of serotonin is the amino acid tryptophan. Peptide transmitters, or neuropeptides, are protein transmitters that often are released together with other transmitters to have a modulatory effect.^[3] Purine neurotransmitters, like ATP, are derived from nucleic acids. Other neurotransmitters are made up of metabolic products like nitric oxide and carbon monoxide.^{[citation needed]}

Storage

Neurotransmitters are generally stored in synaptic vesicles, clustered close to the cell membrane at the axon terminal of the presynaptic neuron. However, some neurotransmitters, like the metabolic gases carbon monoxide and nitric oxide, are synthesized and released immediately following an action potential without ever being stored in vesicles.^[4]

Release

Generally, a neurotransmitter is released at the presynaptic terminal in response to an electrical signal called an action potential in the presynaptic neuron. However, low level 'baseline' release also occurs without electrical stimulation. Neurotransmitters are released into and diffuse across the synaptic cleft, where they bind to specific receptors on the membrane of the postsynaptic neuron.^[5]

Receptor interaction

After being released into the synaptic cleft, neurotransmitters diffuse across the synapse where they are able to interact with receptors on the target cell. The effect of the neurotransmitter is dependent on the identity of the target cell's receptors present at the synapse. Depending on the receptor, binding of neurotransmitters may cause excitation, inhibition, or modulation of the postsynaptic neuron. See below for more information.^{[citation needed]}

Elimination

In order to avoid continuous activation of receptors on the post-synaptic or target cell, neurotransmitters must be removed from the synaptic cleft.^[6] Neurotransmitters are removed through one of three mechanisms:

1. Diffusion – neurotransmitters drift out of the synaptic cleft, where they are absorbed by glial cells. These glial cells, usually astrocytes, absorb the excess neurotransmitters.
   • Astrocytes, a type of glial cell in the brain, actively contribute to synaptic communication through astrocytic diffusion or gliotransmission. Neuronal activity triggers an increase in astrocytic calcium levels, prompting the release of gliotransmitters, such as glutamate, ATP, and D-serine.These gliotransmitters diffuse into the extracellular space, interacting with nearby neurons and influencing synaptic transmission. By regulating extracellular neurotransmitter levels, astrocytes help maintain proper synaptic function. This bidirectional communication between astrocytes and neurons add complexity to brain signaling, with implications for brain function and neurological disorders.^[7][8]
2. Enzyme degradation – proteins called enzymes break the neurotransmitters down.
3. Reuptake – neurotransmitters are reabsorbed into the pre-synaptic neuron. Transporters, or membrane transport proteins, pump neurotransmitters from the synaptic cleft back into axon terminals (the presynaptic neuron) where they are stored for reuse.

For example, acetylcholine is eliminated by having its acetyl group cleaved by the enzyme acetylcholinesterase; the remaining choline is then taken in and recycled by the pre-synaptic neuron to synthesize more acetylcholine.^[9] Other neurotransmitters are able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at regulatory points, which may be targeted by the body's regulatory system or medication. Cocaine blocks a dopamine transporter responsible for the reuptake of dopamine. Without the transporter, dopamine diffuses much more slowly from the synaptic cleft and continues to activate the dopamine receptors on the target cell.^[10]

Discovery

Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through histological examinations by Ramón y Cajal, a 20 to 40 nm gap between neurons, known today as the synaptic cleft, was discovered. The presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, and in 1921 German pharmacologist Otto Loewi confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is credited with discovering acetylcholine (ACh) – the first known neurotransmitter.^[11]

Identification

To identify neurotransmitters, the following criteria are typically considered:

1. Synthesis: The chemical must be produced within the neuron or be present in it as a precursor molecule.
2. Release and Response: When the neuron is activated, the chemical must be released and elicit a response in target cells or neurons.
3. Experimental Response: Application of the chemical directly to the target cells should produce the same response observed when the chemical is naturally released from neurons.
4. Removal Mechanism: There must be a mechanism in place to remove the neurotransmitter from its site of action once its signaling role is complete.^[12]

However, given advances in pharmacology, genetics, and chemical neuroanatomy, the term "neurotransmitter" can be applied to chemicals that:

• Carry messages between neurons via influence on the postsynaptic membrane.
• Have little or no effect on membrane voltage, but have a common carrying function such as changing the structure of the synapse.
• Communicate by sending reverse-direction messages that affect the release or reuptake of transmitters.

The anatomical localization of neurotransmitters is typically determined using immunocytochemical techniques, which identify the location of either the transmitter substances themselves or of the enzymes that are involved in their synthesis. Immunocytochemical techniques have also revealed that many transmitters, particularly the neuropeptides, are co-localized, that is, a neuron may release more than one transmitter from its synaptic terminal.^[13] Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system.^[14]

Actions

Neurons communicate with each other through synapses, specialized contact points where neurotransmitters transmit signals. When an action potential reaches the presynaptic terminal, the action potential can trigger the release of neurotransmitters into the synaptic cleft. These neurotransmitters then bind to receptors on the postsynaptic membrane, influencing the receiving neuron in either an inhibitory or excitatory manner. If the overall excitatory influences outweigh the inhibitory influences, the receiving neuron may generate its own action potential, continuing the transmission of information to the next neuron in the network. This process allows for the flow of information and the formation of complex neural networks.^[15]

Modulation

A neurotransmitter may have an excitatory, inhibitory or modulatory effect on the target cell. The effect is determined by the receptors the neurotransmitter interacts with at the post-synaptic membrane. Neurotransmitter influences trans-membrane ion flow either to increase (excitatory) or to decrease (inhibitory) the probability that the cell with which it comes in contact will produce an action potential. Synapses containing receptors with excitatory effects are called Type I synapses, while Type II synapses contain receptors with inhibitory effects.^[16] Thus, despite the wide variety of synapses, they all convey messages of only these two types. The two types are different appearance and are primarily located on different parts of the neurons under its influence.^[17] Receptors with modulatory effects are spread throughout all synaptic membranes and binding of neurotransmitters sets in motion signaling cascades that help the cell regulate its function.^[18] Binding of neurotransmitters to receptors with modulatory effects can have many results. For example, it may result in an increase or decrease in sensitivity to future stimulus by recruiting more or less receptors to the synaptic membrane.

Type I (excitatory) synapses are typically located on the shafts or the spines of dendrites, whereas type II (inhibitory) synapses are typically located on a cell body. In addition, Type I synapses have round synaptic vesicles, whereas the vesicles of type II synapses are flattened. The material on the presynaptic and post-synaptic membranes is denser in a Type I synapse than it is in a Type II, and the Type I synaptic cleft is wider. Finally, the active zone on a Type I synapse is larger than that on a Type II synapse.

The different locations of Type I and Type II synapses divide a neuron into two zones: an excitatory dendritic tree and an inhibitory cell body. From an inhibitory perspective, excitation comes in over the dendrites and spreads to the axon hillock to trigger an action potential. If the message is to be stopped, it is best stopped by applying inhibition on the cell body, close to the axon hillock where the action potential originates. Another way to conceptualize excitatory–inhibitory interaction is to picture excitation overcoming inhibition. If the cell body is normally in an inhibited state, the only way to generate an action potential at the axon hillock is to reduce the cell body's inhibition. In this "open the gates" strategy, the excitatory message is like a racehorse ready to run down the track, but first, the inhibitory starting gate must be removed.^[19]

Neurotransmitter actions

As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the receptors.

• Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain. Excessive glutamate release can overstimulate the brain and lead to excitotoxicity causing cell death resulting in seizures or strokes.^[20] Excitotoxicity has been implicated in certain chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington disease, and Parkinson's disease.^[21]
• GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA.^[22] Correspondingly, glycine is the inhibitory transmitter in the spinal cord.
• Acetylcholine was the first neurotransmitter discovered in the peripheral and central nervous systems. It activates skeletal muscles in the somatic nervous system and may either excite or inhibit internal organs in the autonomic system.^[14] It is distinguished as the transmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also operates in many regions of the brain, but using different types of receptors, including nicotinic and muscarinic receptors.^[23]
• Dopamine has a number of important functions in the brain; this includes regulation of motor behavior, pleasures related to motivation and also emotional arousal. It plays a critical role in the reward system; Parkinson's disease has been linked to low levels of dopamine and schizophrenia has been linked to high levels of dopamine.^[24]
• Serotonin is a monoamine neurotransmitter. Most is produced by and found in the intestine (approximately 90%), and the remainder in central nervous system neurons. It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and endocrine system. It is speculated to have a role in depression, as some depressed patients are seen to have lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.^[25]
• Norepinephrine is a member of the catecholamine classification of neurotransmitters. It is synthesized from the amino acid tyrosine. In the peripheral nervous system, one of the primary roles of norepinephrine is to stimulate the release of the stress hormone epinephrine (i.e. adrenaline) from the adrenal glands.^[26]
• Epinephrine, a neurotransmitter and hormone is synthesized from tyrosine. It is released from the adrenal glands and plays a role in the fight-or-flight response. Epinephrine has vasoconstrictive effects, which promote increased heart rate, blood pressure, energy mobilization. Vasoconstriction influences metabolism by promoting the breakdown of glucose released into the bloodstream. Epinephrine also has bronchodilation effects, which is the relaxing of airways.^[26]

Types

There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and monoamines is sufficient for some classification purposes.^[27]

Major neurotransmitters:

• Amino acids: glutamate,^[28] aspartate, D-serine, gamma-Aminobutyric acid (GABA),^{[nb 1]} glycine
• Gasotransmitters: nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H₂S)
• Monoamines:
  • Catecholamines: dopamine (DA), norepinephrine (noradrenaline, NE), epinephrine (adrenaline)
  • Indolamines: serotonin (5-HT, SER), melatonin
  • histamine
• Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, octopamine, tryptamine, etc.
• Peptides: oxytocin, somatostatin, substance P, cocaine and amphetamine regulated transcript, opioid peptides^[29]
• Purines: adenosine triphosphate (ATP), adenosine
• Others: acetylcholine (ACh), anandamide, etc.

In addition, over 100 neuroactive peptides have been found, and new ones are discovered regularly.^[30][31] Many of these are co-released along with a small-molecule transmitter. Nevertheless, in some cases, a peptide is the primary transmitter at a synapse. Beta-Endorphin is a relatively well-known example of a peptide neurotransmitter because it engages in highly specific interactions with opioid receptors in the central nervous system.

Single ions (such as synaptically released zinc) are also considered neurotransmitters by some,^[32] as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S).^[33] The gases are produced in the neural cytoplasm and are immediately diffused through the cell membrane into the extracellular fluid and into nearby cells to stimulate production of second messengers. Soluble gas neurotransmitters are difficult to study, as they act rapidly and are immediately broken down, existing for only a few seconds.

The most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain.^[28] The next most prevalent is gamma-Aminobutyric Acid, or GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Although other transmitters are used in fewer synapses, they may be very important functionally: the great majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamines exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.

List of neurotransmitters, peptides, and gaseous signaling molecules

This list is incomplete; you can help by adding missing items. (January 2017)