All neuromodulators (dopamine, serotonin, acetylcholine, histamine, and norepinephrine) act only on metabotropic receptors?

All neuromodulators (dopamine, serotonin, acetylcholine, histamine, and norepinephrine) act only on metabotropic receptors?

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All neuromodulators like dopamine, serotonin, acetylcholine, histamine, and norepinephrine act only on metabotropic receptors?

Not all neuromodulators act only on metabotropic receptors. However, you are correct to observe that this is a general rule of thumb.

Of the substances you have listed:

  • Acetylcholine is not primarily a neuromodulator, but rather a "normal" neurotransmitter. As such it acts on both ionotropic and metabotropic receptors.

  • Serotonin - the one exception among the neuromodulators you have listed - acts on numerous classes of metabotropic receptors, but also on the 5-HT3 receptor, which is ionotropic.

  • All other neuromodulators you have listed act on metabotropic receptors only.

This tendency of neuromodulation to be metabotropically mediated is possibly a consequence of the nature of the neuronal function itself. Neuromodulatory systems do not per se relay information, but change how other information relays work. As such there is no need for the most rapid, temporal, coding (best achieved via the more rapid ionotropic signal transduction), and a slower coding may even be more efficient.

All neuromodulators (dopamine, serotonin, acetylcholine, histamine, and norepinephrine) act only on metabotropic receptors? - Biology

Microglia express receptors for neuromodulators in vivo and in culture.

Neuromodulators modulate microglial cell motility, phagocytic activity, migration.

Neuromodulators modulate microglial immune polarization.

Some of the effects of neuromodulators on CNS development and homeostasis might be performed through their modulation of microglia.


The major neurotransmitter systems are the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system. Drugs targeting the neurotransmitter of such systems affects the whole system, and explains the mode of action of many drugs.

Most other neurotransmitters, on the other hand, e.g. glutamate, GABA and glycine, are used very generally throughout the central nervous system.

  • arousal (Arousal is a physiological and psychological state of being awake or reactive to stimuli)
  • mesocortical pathway
  • mesolimbic pathway
  • nigrostriatal pathway
  • tuberoinfundibular pathway
  • deep cerebellar nuclei
  • cerebellar cortex
  • increase (introversion): [clarification needed]
    • mood
    • satiety
    • body temperature
  • deep cerebellar nuclei ⎖]
  • pontine nuclei ⎖]
  • locus ceruleus ⎖]
  • raphe nucleus ⎖]
  • lateral reticular nucleus ⎖]
  • inferior olive ⎖]⎗]
  • tectum ⎗]⎗]⎗]
    • muscle and motor control system
    • arousal
    • reward

    Noradrenaline system

    The noradrenaline system consists of around 15,000 neurons, primarily in the locus coeruleus. ⎘] This is diminutive compared to the more than 100 billion neurons in the brain. As with dopaminergic neurons in the substantia nigra, neurons in the locus coeruleus tend to be melanin-pigmented. Noradrenaline is released from the neurons, and acts on adrenergic receptors. Noradrenaline is often released steadily so that it can prepare the supporting glial cells for calibrated responses. Despite containing a relatively small number of neurons, when activated, the noradrenaline system plays major roles in the brain including involvement in suppression of the neuroinflammatory response, stimulation of neuronal plasticity through LTP, regulation of glutamate uptake by astrocytes and LTD, and consolidation of memory. ⎙]

    Dopamine system

    The dopamine or dopaminergic system consists of several pathways, originating from the ventral tegmentum or substantia nigra as examples. It acts on dopamine receptors. ⎚]

    Parkinson's disease is at least in part related to dropping out of dopaminergic cells in deep-brain nuclei, primarily the melanin-pigmented neurons in the substantia nigra but secondarily the noradrenergic neurons of the locus coeruleus. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.

    Dopamine pharmacology

      , for example, blocks the reuptake of dopamine, leaving these neurotransmitters in the synaptic gap longer. prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine reserpine prevents dopamine storage within vesicles and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.

    Serotonin system

    The serotonin created by the brain comprises around 10% of total body serotonin. The majority (80-90%) is found in the gastrointestinal (GI) tract. ⎛] ⎜] It travels around the brain along the medial forebrain bundle and acts on serotonin receptors. In the peripheral nervous system (such as in the gut wall) serotonin regulates vascular tone.

    Serotonin pharmacology

      (SSRIs) such as fluoxetine are widely used antidepressants that specifically block the reuptake of serotonin with less effect on other transmitters. ⎝]⎞]⎟]
    • Tricyclic antidepressants also block reuptake of biogenic amines from the synapse, but may primarily effect serotonin or norepinephrine or both. They typically take 4 to 6 weeks to alleviate any symptoms of depression. They are considered to have immediate and long-term effects. ⎝]⎟]⎠]
    • Monoamine oxidase inhibitors allow reuptake of biogenic amine neurotransmitters from the synapse, but inhibit an enzyme which normally destroys (metabolizes) some of the transmitters after their reuptake. More of the neurotransmitters (especially serotonin, noradrenaline and dopamine) are available for release into synapses. MAOIs take several weeks to alleviate the symptoms of depression. ⎝]⎟]⎡]⎢]

    Although changes in neurochemistry are found immediately after taking these antidepressants, symptoms may not begin to improve until several weeks after administration. Increased transmitter levels in the synapse alone does not relieve the depression or anxiety. ⎝] ⎟] ⎢]

    Cholinergic system

    The cholinergic system consists of projection neurons from the pedunculopontine nucleus, laterodorsal tegmental nucleus, and basal forebrain and interneurons from the striatum and nucleus accumbens. It is not yet clear whether acetylcholine as a neuromodulator acts through volume transmission or classical synaptic transmission, as there is evidence to support both theories. Acetylcholine binds to both metabotropic muscarinic receptors (mAChR) and the ionotropic nicotinic receptors (nAChR). The cholinergic system has been found to be involved in responding to cues related to the reward pathway, enhancing signal detection and sensory attention, regulating homeostasis, mediating the stress response, and encoding the formation of memories. ⎣] ⎤]

    Gamma-aminobutyric acid (GABA) has an inhibitory effect on brain and spinal cord activity. ⎝]


    Neuropeptides are small proteins used for communication in the nervous system. Neuropeptides represent the most diverse class of signaling molecules. There are 90 known genes that encode human neuropeptide precursors. In invertebrates, there are

    50 known genes encoding neuropeptide precursors. ⎥] Most neuropeptides bind to G-protein coupled receptors, however some neuropeptides directly gate ion channels or act through kinase receptors.

    • Opioid peptides – a large family of endogenous neuropeptides that are widely distributed throughout the central and peripheral nervous system. Opiate drugs such as heroin and morphine act at the receptors of these neurotransmitters. ⎦]⎧]

    Epinephrine and norepinephrine

    These related hormones, also called adrenaline (epinephrine) and noradrenaline (norepinephrine), act to increase the heart rate, blood pressure, and levels of sugar and fat in the blood. They are secreted into the bloodstream by the adrenal glands in response to stress, but they are also synthesized and released as neurotransmitters by axon terminals in the central nervous system and in sympathetic fibres of the autonomic nervous system.

    Receptors sensitive to norepinephrine and epinephrine are called adrenergic receptors. They are divided into two types, α and β. These are further classified into subtypes α1, α2, β1, and β2.

    Both types of adrenergic receptors produce changes in the postsynaptic membrane potential by acting upon ion channels specific to K + and Ca 2+ . They differ in the mechanisms that, upon stimulation by neurotransmitter, they employ to activate those channels. Stimulated β1 receptors bind to linking proteins that in turn bind to calcium channels, changing their shape and altering their permeability to the cation. More important, the linking proteins stimulate the synthesis of cAMP, which, through another series of reactions, opens potassium channels. The efflux of K + tends to hyperpolarize the postsynaptic membrane, inhibiting the generation of a nerve impulse. The β2 receptor has been found on glial cells.

    The α2 receptor activates potassium channels in both the postsynaptic and presynaptic membranes, probably via linking proteins and the synthesis of cAMP. The α1 receptor acts on calcium channels through a series of reactions linked to the lipid molecules of the plasma membrane.

    Both epinephrine and norepinephrine are terminated by uptake back into the presynaptic terminals, where they are enzymatically degraded or inactivated.


    Chemical messengers bind to metabotropic receptors to initiate a diversity of effects caused by biochemical signaling cascades. G protein-coupled receptors are all metabotropic receptors. When a ligand binds to a G protein-coupled receptor, a guanine nucleotide-binding protein, or G protein, activates a second messenger cascade which can alter gene transcription, regulate other proteins in the cell, release intracellular Ca 2+ , or directly affect ion channels on the membrane. [2] [3] These receptors can remain open from seconds to minutes and are associated with long-lasting effects, such as modifying synaptic strength and modulating short- and long-term synaptic plasticity. [4]

    Metabotropic receptors have a diversity of ligands, including but not limited to: small molecule transmitters, monoamines, peptides, hormones, and even gases. [4] [5] [6] In comparison to fast-acting neurotransmitters, these ligands are not taken up again or degraded quickly. They can also enter the circulatory system to globalize a signal. [2] Most metabotropic ligands have unique receptors. Some examples include: metabotropic glutamate receptors, muscarinic acetylcholine receptors, GABAB receptors. [1] [7]

    The G protein-coupled receptors have seven hydrophobic transmembrane domains. Most of them are monomeric proteins, although GABAB receptors require heterodimerization to function properly. The protein's N terminus is located on the extracellular side of the membrane and its C terminus is on the intracellular side. [1]

    The 7 transmembrane spanning domains, with an external amino terminus, are often claimed as being alpha helix shaped, and the polypeptide chain is said to be composed of

    4.2 Neurochemical Transmitters and Receptors

    Now that you know how neurotransmission occurs, it is time to learn about some of the neurotransmitters that are used in the human body. There are many more neurotransmitters than what is included in this section (possibly up to one hundred) the ones selected are some of the most prevalent and well-researched. Most of these will be affected in some way by the drugs that we will examine later in the course.

    There is a lot of material in this section, but don’t worry at the end of the section, there will be a table that will give you an overview of all the important information. As you read this section, try to associate the name of each neurotransmitter with its function once you reach the end, you will be able to go over all the receptors and categories again, and organizing everything will be easier once you have a sense of what each term means.

    By the end of this section, you should be able to:

    • Provide examples of neurochemical transmitters, their general functions, and the receptors they activate.
    • Explain the classification of various types of neurotransmitters, including monoamines, amino acids, peptides, and gaseous signaling molecules.

    4.2.1 Acetylcholine

    In this subsection, we will look at acetylcholine, the first neurotransmitter identified. This was the chemical involved in Otto Loewi’s experiment that he named vagusstoff. Acetylcholine had already been discovered in biological organisms by then, and Loewi and other researchers suspected that vagusstoff was acetylcholine, although it took a few years before this was verified.

    In the PNS, acetylcholine plays a large role in the parasympathetic nervous system. Recall that in Loewi’s experiment, the vagusstoff caused the heart rate to slow. This is one of the many effects that acetylcholine is responsible for, along with other “rest and digest” responses such as pupil constriction and innervating smooth muscle. Acetylcholine is also the neurotransmitter that activates skeletal muscle in the somatic nervous system, meaning your voluntary movements are all regulated by this neurotransmitter.

    In the CNS, acetylcholine plays an important role in processing memories. In the hippocampus, damage to acetylcholine receptors is associated with the memory loss seen in people with Alzheimer’s disease. The neurotransmitter is also involved in attention and arousal.

    Acetylcholine receptors are called cholinergic receptors. In this context, the -ergic suffix means “activated by,” so the term cholinergic just means “activated by choline.” (Choline is one of the chemicals that acetylcholine is made out of, which is why it’s in the name.) There are two types of cholinergic receptors: muscarinic and nicotinic. Both are named after drugs that produced a different subset of the effects that acetylcholine does. As you can probably guess, nicotinic receptors are activated by nicotine, which will be cover in detail by this class.

    4.2.2 Norepinephrine, Epinephrine, and Dopamine

    In this subsection we will cover catecholamines, which are organic compounds that have a catechol (benzene ring with two hydroxyl side groups) connected by two carbons to a single amine (NH) group. You don’t need to memorize the molecular structure of each neurotransmitter for this class, but, by examining the chemical structures below, you can see similarities between each of the neurotransmitters in this class.

    The first catecholamine we will discuss is epinephrine. In the UK and Europe, epinephrine is called adrenaline, which probably gives you a sense of what epinephrine does. We often talk about getting a rush of adrenaline in fight-or-flight situations, so as you might expect, epinephrine is involved the sympathetic nervous system. Epinephrine can dilate the pupils and increase blood flow from the heart to the muscles. It is a hormone that is produced by the adrenal glands and activates adrenergic receptors, of which there are two main types called alpha (α) and beta (β) adrenergic receptors. You might also see adrenergic receptors called adrenoreceptors, which is just a shorter name for the same thing.

    A very similar chemical is called norepinephrine, which is also called noradrenaline internationally. The nor- prefix comes from the fact that in this molecule, the CH3 group is missing. Similar to epinephrine, it is involved in the sympathetic response and activates α and β adrenergic receptors.

    Unlike epinephrine, which is released solely as a hormone, norepinephrine is released as both a hormone and a typical neurotransmitter. In the CNS, it plays a role in arousal and attention and is important in mood regulation. A deficiency in norepinephrine can be a component to certain types of depression, which we will cover in detail when we discuss antidepressants.

    What is the difference between a hormone and neurotransmitter?

    We mentioned that epinephrine is a hormone secreted by the adrenal gland, but what exactly is a hormone? Hormones are produced in organs called glands and are secreted into the bloodstream. Compare this to most neurotransmitters, which are produced inside the axon terminal of neurons and released into the synaptic cleft. The big difference is range: hormones are circulated throughout the body and can reach distant target cells, while neurotransmitters are limited to the synapse.

    Although there is a clear line between hormones and neurotransmitters in terms of function, some chemicals can behave as neurotransmitters in some cases and hormones in others. If you are interested in learning more (it is not required for this class), a good place to start is this brief writeup by Alpana and Murari Chaudhuri:

    The third and final catecholamine is dopamine. Dopamine is a very important component of drug dependence, as one of dopamine’s main roles in the CNS is reward and reinforcement. The addictive properties of many drugs come from how the drugs stimulate dopamine release and create long-term changes in dopamine-related pathways in the brain. Dopamine is also involved in motor control, and two well-known neurological disorders, Parkinson’s disease and Huntington’s disease, are caused by a deficiency (Parkinson’s) or excess (Huntington’s) in dopamine activity in the basal ganglia. The psychiatric disorder schizophrenia is also caused by an excess of dopamine activity in the limbic system.

    Dopamine activates dopaminergic receptors, of which there are at least five different subtypes.

    4.2.3 Serotonin and Histamine

    The three catecholamines mentioned above are actually a subset of a larger group of neurotransmitters called monoamines. As their name suggests, monoamines have a single amino group, which is connected to an aromatic ring by a two-carbon chain. It is less important that you are able to explain the molecular structure of monoamines instead, you should be able to name five neurotransmitters that are classified as monoamines—the three catecholamines listed above, the two covered below.

    The fourth monoamine is serotonin. The full name for serotonin is 5-hydroxytryptamine, or 5-HT for short. You will often see serotonin called 5-HT in the scientific literature, so it is worth remembering.

    In the PNS, serotonin plays a large role in digestion. Most of the serotonin produced in the body is found in the digestive tract, where it regulates intestinal movement, gastric acid secretion, and mucus production. In the CNS, serotonin is linked to numerous functions, including sleep, anxiety, mood, appetite, nausea, and social and sexual behavior. Similar to norepinephrine, one type of depression is classified as being due to a deficiency in serotonin. 5-HT also plays a major role in the genesis of anxiety.

    Serotonin receptors are called 5-HT receptors they are the most abundant in the human body and contain the most subtypes out of all receptors. They are grouped into 7 main types, labeled 5-HT1 to 5-HT7, and each of those can be distinguished further into subtypes like 5-HT1A.

    The last monoamine we will cover is histamine. (There are other monoamines, but we will focus on these five for this class.) In the PNS, histamine is a part of the inflammatory response, which helps the immune system fight pathogens. This response is what causes itching, sneezing, and a runny nose when you have a cold. In the CNS, histamine is involved in a variety of effects, the most important of which is promoting wakefulness. This is why antihistamine medication is well-known for its sleep-inducing properties. Histamine acts at four main H receptors, H1 to H4, all of which are metabotropic.

    4.2.4 Glutamate, GABA, and Glycine

    The next group of neurotransmitters are the amino acid transmitters. You may recall learning that amino acids are the building blocks of proteins. There are a few amino acids that also act as neurotransmitters. In this subsection, we will look at the three most important ones.

    The first is glutamate, which is the main excitatory neurotransmitter in the CNS. It is involved in various cognitive functions like learning and memory. It is also implicated in neurological conditions such as Alzheimer’s disease, Parkinson’s disease, and epilepsy through a process called excitotoxicity, where overstimulation of glutamate receptors can result in cell degradation and eventually cell death.

    The three main glutamate receptors are all ionotropic and are called AMPA, kainate, and NMDA receptors. The latter is of particular interest to this class, since NMDA receptors are the target sites for certain psychoactive substances like PCP and ketamine.

    The next neurotransmitter is called gamma-aminobutyric acid, or GABA for short, and it is very important for this class. It is the main inhibitory neurotransmitter in the brain, meaning that glutamate and GABA have opposing effects. In fact, some scientists claim that glutamate and GABA are the only two neurotransmitters in the brain in this view, other neurotransmitters are considered neuromodulators, since they enhance or reduce glutamate and GABA transmission. GABA acts at two receptor subtypes, called GABAA and GABAB, to dampen overactive neurons. Many sedatives and tranquilizers achieve their effects by enhancing GABA transmission in some way. Because it is involved in a wide variety of CNS depressants, including alcohol, we will cover GABA and its receptors in more detail in a later chapter.

    Finally, whereas GABA is the main inhibitory transmitter of the brain, glycine is the main inhibitory transmitter in the spinal cord, although it is also present in the brainstem and retina. It has a single receptor simply called the glycine receptor (GlyR) and aside from its role as an inhibitor like GABA, it is also involved in processing motor and sensory information.

    4.2.5 Endorphins and Substance P

    So far, all the neurotransmitters we’ve covered are considered small molecule transmitters, since their molecular structure is relatively small. Neurotransmitters can be much larger, however. Such transmitters are called peptides or neuropeptides peptide means that they are comprised of a chain of amino acids, similar to proteins (although much less complex). We will cover two types of relevant neuropeptides: endorphins and Substance P.

    The first type of peptides we will look at are the endorphins, of which there are three types: alpha, beta, and gamma (γ). Above you can see the structure of β-endorphin—clearly, it is much larger than all of the neurotransmitters we have looked at so far. β-endorphin consists of 31 aino acids. Endorphins act at opioid receptors, of which there are also three types: mu (μ), kappa (κ), and delta (δ). You have probably heard of opioids such a morphine, heroin, oxycodone, and fentanyl. In fact, the name endorphin comes from a contraction of endogenous morphine, since they occur naturally in the body. They are also called endogenous opioid peptides.

    Like opioids, endorphins are noted for producing an analgesic (pain-blocking) effect. This is because the activation of opioid receptors inhibits the release of Substance P, which we will discuss next. In the PNS, endorphins (mostly β-endorphin) are secreted by the pituitary gland and act as hormones. In the CNS, endorphins also trigger feelings of pleasure by inhibiting GABA, which in turn increases dopamine activity in the reward center. The euphoric sensations that occur from listening to music, eating something delicious, sex, or vigorous aerobic exercise (known as a “runner’s high”) are all the result of endorphin activity.

    Two other common endogenous opioid peptides are the enkephalins, which consists of five amino acids, and the dynorphins, which are 13- and 17-amino acid fragments of a larger 32-amino acid precursor.

    As previous mentioned, endorphins can inhibit the release of Substance P, which is involved in transmitting pain signals to the CNS. It was the first neuropeptide ever discovered consisting of a chain of eleven amino acids. Although you might assume the P in the name stands for pain, it actually stands for powder, since it was originally discovered and purified in powder form (Hochberg et al., 2019). Substance P is released from the ends of sensory nerves and activates neurokinin-1 (NK1) receptors.

    4.2.6 Nitric Oxide

    Aside from small molecule neurotransmitters and peptides, there is a third type of transmitter called gaseous signaling molecules or gasotransmitters. These are gas molecules that can freely permeate cell membranes—instead of binding to receptors on the surface of a cell like all of the neurotransmitters discussed previously, these molecules simply cross the membrane on their own and alter cell physiology directly inside the cell. Because they can permeate cell membranes, they cannot be stored in vesicles like other neurotransmitters and instead are produced on demand. Gaseous signaling molecules are recent discoveries in neurotransmission and a lot is currently unknown about them, so we will only look at one type that has been studied the most.

    Nitric oxide (abbreviated NO) is a molecule comprised of a single nitrogen atom coupled to a single oxygen atom. NO is a free radical, meaning it has an unpaired electron. The “receptors” that it binds to are actually enzymes inside the cell, of which the most researched is soluble guanylate cyclase (SGC). When nitric oxide binds to the enzyme, it triggers a signal cascade that leads to the relaxation of smooth muscle. Because of this, a common use of nitric oxide is to dilate blood vessels, increasing blood supply.

    Nitric oxide also plays a role in the immune system, as it is toxic to cellular organisms and can be secreted in response to pathogens. Studies have suggested that it can inhibit the replication of certain viruses, including SARS (Åkerström et al., 2005), which has led to nitric oxide being proposed as a potential treatment to COVID-19 by mitigating pulmonary symptoms and inhibiting the replication of the virus (Adusumilli et al., 2020 Pieretti et al., 2021).

    4.2.7 Transmitters and Receptors Review

    Phew, that was a lot to cover. If you got a little lost at times, it’s okay—there were a lot of new terms being thrown around. To learn this material and organize it in your head, you will have to start by memorizing the associations between the neurotransmitters, their receptors, and their functions. Creating flash cards is a great way to practice and form those connections.

    To help, below is a chart that summarizes all of the important information from this section. You may also want to watch this video from Khan Academy, which covers most of the neurotransmitters from this section:

    External links

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    Neuroscience For Kids

    Communication of information between neurons is accomplished by movement of chemicals across a small gap called the synapse. Chemicals, called neurotransmitters, are released from one neuron at the presynaptic nerve terminal. Neurotransmitters then cross the synapse where they may be accepted by the next neuron at a specialized site called a receptor. The action that follows activation of a receptor site may be either depolarization (an excitatory postsynaptic potential) or hyperpolarization (an inhibitory postsynaptic potential). A depolarization makes it MORE likely that an action potential will fire a hyperpolarization makes it LESS likely that an action potential will fire.

    Discovery of Neurotransmitters

    In 1921, an Austrian scientist named Otto Loewi discovered the first neurotransmitter. In his experiment (which came to him in a dream), he used two frog hearts. One heart (heart #1) was still connected to the vagus nerve. Heart #1 was placed in a chamber that was filled with saline. This chamber was connected to a second chamber that contained heart #2. So, fluid from chamber #1 was allowed to flow into chamber #2. Electrical stimulation of the vagus nerve (which was attached to heart #1) caused heart #1 to slow down. Loewi also observed that after a delay, heart #2 also slowed down. From this experiment, Loewi hypothesized that electrical stimulation of the vagus nerve released a chemical into the fluid of chamber #1 that flowed into chamber #2. He called this chemical "Vagusstoff". We now know this chemical as the neurotransmitter called acetylcholine.

    Otto Loewi's Experiment

    Neurotransmitter Criteria

    Neuroscientists have set up a few guidelines or criteria to prove that a chemical is really a neurotransmitter. Not all of the neurotransmitters that you have heard about may actually meet every one of these criteria.

    The chemical must be produced within a neuron.
    The chemical must be found within a neuron.
    When a neuron is stimulated (depolarized), a neuron must release the chemical.
    When a chemical is released, it must act on a post-synaptic receptor and cause a biological effect.
    After a chemical is released, it must be inactivated. Inactivation can be through a reuptake mechanism or by an enzyme that stops the action of the chemical.
    If the chemical is applied on the post-synaptic membrane, it should have the same effect as when it is released by a neuron.

    Neurotransmitter Types

    There are many types of chemicals that act as neurotransmitter substances. Below is a list of some of them.

    Small Molecule Neurotransmitter Substances

    Amino Acids

    Neuroactive Peptides - partial list only!

    bradykinin beta-endorphin bombesin calcitonin
    cholecystokinin enkephalin dynorphin insulin
    gastrin substance P neurotensin glucagon
    secretin somatostatin motilin vasopressin
    oxytocin prolactin thyrotropin angiotensin II
    sleep peptides galanin neuropeptide Y thyrotropin-releasing hormone
    gonadotropnin-releasing hormone growth hormone-releasing hormone luteinizing hormone vasoactive intestinal peptide

    Soluble Gases

    Synthesis of Neurotransmitters

    Acetylcholine is found in both the central and peripheral nervous systems. Choline is taken up by the neuron. When the enzyme called choline acetyltransferase is present, choline combines with acetyl coenzyme A (CoA) to produce acetylcholine.

    Dopamine, norepinephrine and epinephrine are a group of neurotransmitters called "catecholamines". Norepinephrine is also called "noradrenalin" and epinephrine is also called "adrenalin". Each of these neurotransmitters is produced in a step-by-step fashion by a different enzyme.

    Transport and Release of Neurotransmitters

    Neurotransmitters are made in the cell body of the neuron and then transported down the axon to the axon terminal. Molecules of neurotransmitters are stored in small "packages" called vesicles (see the picture on the right). Neurotransmitters are released from the axon terminal when their vesicles "fuse" with the membrane of the axon terminal, spilling the neurotransmitter into the synaptic cleft.

    Unlike other neurotransmitters, nitric oxide (NO) is not stored in synaptic vesicles. Rather, NO is released soon after it is produced and diffuses out of the neuron. NO then enters another cell where it activates enzymes for the production of "second messengers."

    Receptor Binding

    Neurotransmitters will bind only to specific receptors on the postsynaptic membrane that recognize them.

    Inactivation of Neurotransmitters

    The action of neurotransmitters can be stopped by four different mechanisms:

    All neuromodulators (dopamine, serotonin, acetylcholine, histamine, and norepinephrine) act only on metabotropic receptors? - Biology

    There are two kinds of receptors:

    ionotropic receptors are ion channels to which neurotransmitters bind directly in order to open them.

    In contrast, metabotropic receptors are separate from the ion channels whose operation they regulate. They make the linkage by means of a membrane protein from the G-protein family.


    Thanks to research by hundreds of laboratories throughout the world, the main entities involved in synaptic transmission have now been identified. They include over sixty neurotransmitters and hundreds of subtypes of receptors. Since a single neuron may release several different neurotransmitters at once, the soup of molecules and ions in the synaptic gap can be decoded only by means of very specific affinities between neurotransmitters and their receptors.

    A combination of neurotransmitters that can act on various subtypes of receptors can thus have varying effects, depending on what particular receptors they are acting upon.

    This diagram shows a synapse that is capable of long-term potentiation, a synaptic facilitation mechanism that is the basis for memory. The neurotransmitter involved here is glutamate. The enlarged diagram shows just three of the approximately twenty known subtypes of glutamate receptors.

    When glutamate binds to these receptors, it not only causes the ion channels to open but also triggers several cascades of chemical reactions, also represented in this diagram. Many of these reactions involve &ldquosecond messengers:&rdquo molecules that relay signals from neurotransmitters within the postsynaptic neuron and that can in turn cause other ion channels to open or close. The effects of second messengers can extend all the way to the neuron&rsquos nucleus, thus influencing its synthesis of new proteins, receptors, or channels, for example.

    Ion channels too are large proteins embedded in the neuronal membrane. It is the selective opening of all these various channels that, by changing the membrane&rsquos electrical potential, produces the action potential.

    It is also these channels that let calcium ions enter the presynaptic neuron when the action potential reaches the axon&rsquos terminal button&ndasha crucial step that leads to the fusion of the synaptic vesicles with the membrane and their expulsion of neurotransmitters into the synaptic gap.

    Lastly, this overview of the entities involved in neurotransmission would not be complete without a mention of the other transmembrane proteins that reabsorb neurotransmitters into the presynaptic neuron or that actively pump ions through the membrane against their natural gradient.

    Many peptides act more as neuromodulators than as neurotransmitters. Neuromodulators are substances that do not propagate nerve impulses directly, but instead affect the synthesis, breakdown, or reabsorption (reuptake) of neurotransmitters. Neuromodulators can also exert regulatory effects on many extra-synaptic receptors, rather than on synaptic sites exclusively.

    1) It must be produced inside a neuron, found in the neuron&rsquos terminal button, and released into the synaptic gap upon the arrival of an action potential. 2) It must produce an effect on the postsynaptic neuron. 3) After it has transmitted its signal to this neuron, it must be deactivated rapidly. 4) It must have the same effect on the postsynaptic neuron when applied experimentally as it does when secreted by a presynaptic neuron.

    Over 60 different molecules are currently known to meet these criteria.

    Among the small molecules constituting the &ldquoclassical&rdquo neurotransmitters , the best known are:

    • acetylcholine
    • serotonin
    • catecholamines, including epinephrine, norepinephrine, and dopamine
    • excitatory amino acids such as aspartate and glutamate (half of the synapses in the central nervous system are glutamatergic)
    • inhibitory amino acids such as glycine and gamma-aminobutyric acid (GABA one-quarter to one-third of the synapses in the central nervous system are GABAergic)
    • histamine
    • adenosine
    • adenosine triphosphate (ATP)

    Peptides form another large family of neurotransmitters, with over 50 known members. Here is a very partial list:

    • substance P, beta endorphin, enkephalin, somatostatin, vasopressin, prolactin, angiotensin II, oxytocin, gastrin, cholecystokinin, thyrotropin, neuropeptide Y, insulin, glucagon, calcitonin, neurotensin, bradykinin.

    Certain soluble gases also act as neurotransmitters. The most important member of this category is nitrogen monoxide (NO).

    These neurotransmitters act by their own distinctive mechanism: they exit the transmitting neuron&rsquos cell membrane by simple diffusion and penetrate the receiving neuron&rsquos membrane in the same way.