Neurotransmitters, their receptors and their role in pathology

Figure 1. Structure and function of chemical synapses. (A) Structure of a chemical synapse in the cerebral cortex. A presynaptic terminal (pink) forms
a synapse with a postsynaptic dendrite (green). (B) Three-dimensional reconstruction of the synapse shown in (A). Inside the presynaptic terminal,
spheres indicate synaptic vesicles at various stages of their traffcking cycle, linear elements indicate intracellular flaments, and dark blue indicates
dense projections associated with the active zone. Inside the postsynaptic neuron, the blue structure is the postsynaptic density, green structures
represent flaments, red spheres indicate points where the flaments branch. Green material within the synaptic cleft indicates structures of unknown
function. (C) Sequence of events involved in transmission at a typical chemical synapse. (A,B from Burette et al., 2012.)
 Human brain contains about 86.000.000.000 neurons. Clearly, sophisticated and highly efficient mechanisms are
needed to enable communication among this astronomical number of elements. Such communication is made possible by
synapses, the functional contacts between neurons. Two different types of synapses—electrical and chemical—can be
distinguished on the basis of their mechanism of transmission. At electrical synapses, current flows through connexons,
which are specialized membrane channels that connect two cells at gap junctions. In contrast, chemical synapses enable
cell-to-cell communication via the secretion of neurotransmitters; these chemical agents released by the presynaptic neurons
produce secondary current flow in postsynaptic neurons by activating specific neurotransmitter receptors. The total number
of neurotransmitters is well over 100. Virtually all neurotransmitters undergo a similar cycle of use: synthesis and packaging
into synaptic vesicles; release from the presynaptic cell; binding to postsynaptic receptors; and finally, rapid removal or
degradation. The influx of Ca2+ through voltage-gated channels triggers the secretion of neurotransmitters; this, in turn,
gives rise to a transient increase in Ca 2+ concentration in the presynaptic terminal. The rise in Ca 2+ concentration causes
synaptic vesicles to fuse with the presynaptic plasma membrane and release their contents into the space between the pre-
and postsynaptic cells. Proteins on the surface of the synaptic vesicle and the presynaptic plasma membrane mediate the
triggering of exocytosis by Ca2+. Neurotransmitters evoke postsynaptic electrical responses by binding to members of a
diverse group of neurotransmitter receptors. There are two major classes of receptors: those in which the receptor molecule
is also an ion channel (ionotropic receptors, like NMDA receptor for glutamate), and those in which the receptor activates
some metabolic process that later, along with certain other effects may interfere with some ion channel (metabotropic
receptors). Whether the postsynaptic actions of a particular neurotransmitter are excitatory or inhibitory is determined by
the ion permeability of the ion channel affected by the transmitter, and by the electrochemical gradient for the permeant
ions.
In the human brain, most of the neurons communicate with one another, for the most part, by releasing chemical
messengers called neurotransmitters (NTMs). This way of communication seems to be much efficient than relatively rare
electrical transmission since it provides more capabilities for modulation and adjusting the strength of a given contact with
the demands. A large number of NTMs are known. The main excitatory NTM in the brain is the amino acid glutamate,
while the main inhibitory NTM is -aminobutyric acid (GABA). These and all other NTMs evoke postsynaptic responses
by binding to and activating NTM receptors. Most neurotransmitters are capable of activating several different receptors,
yielding many possible modes of synaptic signaling. After activating their postsynaptic receptors, neurotransmitters are
removed from the synaptic cleft by neurotransmitter transporters or by degradative enzymes. Abnormalities in the function
of neurotransmitter systems contribute to a wide range of neurological and psychiatric disorders; thus, many
neuropharmacological therapies are based on drugs that affect neurotransmitters, their receptors, or the mechanisms
responsible for removing neurotransmitters from the synaptic cleft.

Categories of neurotransmitters

There are more than 100 different neurotransmitters. This large number of transmitters allows for tremendous diversity in
chemical signaling between neurons. It is useful to separate this panoply of transmitters into two broad categories based
simply on size. Neuropeptides, also called peptide neurotransmitters, are relatively large transmitter molecules composed
of 3 to 36 amino acids. Individual amino acids, such as glutamate and GABA, as well as the transmitters acetylcholine,
serotonin, and histamine, are much smaller than neuropeptides and have therefore come to be called small-molecule
neurotransmitters (sometimes also called classical NTMs). Within the category of small-molecule neurotransmitters, the
biogenic amines (dopamine, norepinephrine, epinephrine, serotonin, and histamine) are often discussed separately because
of their similar chemical properties and postsynaptic actions. The particulars of synthesis, packaging, release, and removal
differ for each neurotransmitter are provided in a table below.
It is now clear that the “one neuron, one neurotransmitter” postulate is the exception rather than the rule. Indeed,
the corelease of a fast-acting “classical” neurotransmitter and a peptide, nucleotide (e.g., ATP), Zn2+, neurotrophic factor,
nitric oxide, or endogenous cannabinoids––among other modulators––has been established. In all these cases the co-released
factors are synthesized in the cell (except for Zn2+), released in a selectively regulated fashion, act on receptors, and are
removed or inactivated by specific mechanisms. These characteristics help to confer upon the factors the status of
“neurotransmitter,” and they serve a modulatory purpose. On the other hand, the coexistence and co-release of two or more
“classical” neurotransmitters, each conveying a “principal message,” has been studied less extensively and has in some
ways remained a curiosity.
We’ll briefly review some of the most important NTMs, emphasizing their role in pathology.

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 Figure 2. Functional features of the main NTMs

Acetylcholine (ACh) was the first substance identified as a neurotransmitter. In

addition to its function as the neurotransmitter at skeletal neuromuscular junctions,
as well as at the neuromuscular synapse between the vagus nerve and cardiac
muscle fibers, ACh serves as a transmitter at synapses in the ganglia of the visceral
motor system and at a variety of sites in the CNS. Whereas a great deal is known
about the function of cholinergic transmission at neuromuscular junctions and
ganglionic synapses, the actions of ACh in the CNS are not as well understood.

Consistent with the essential role of ACh receptors in mediating muscle contraction
at neuromuscular junctions in numerous species, a large number of natural toxins
interfere with signaling mediated by these receptors. In fact, the classification of
nicotinic and muscarinic ACh receptors is based on the sensitivity of these
Figure 3. The producer of bungarotoxin -
receptors to the toxic plant alkaloids nicotine and muscarine, which activate Bungarus multicinctus.
nicotinic and muscarinic ACh receptors, respectively. Nicotine is derived from the
dried leaves of the tobacco plant Nicotinia tabacum, and muscarine is from the poisonous red mushroom Amanita muscaria. Both
toxins are stimulants that produce nausea, vomiting,
mental confusion, and convulsions. Muscarine
poisoning can also lead to circulatory collapse, coma,
and death. The poison α-bungarotoxin, one of many
peptides that together make up the venom of the banded
krait (Bungarus multicinctus), blocks transmission at
neuromuscular junctions and is used by the snake to
paralyze its prey. In myasthenia gravis, the nicotinic
receptors of Ach become a target of autoimmune attack.
In this disease, the “snake” appears to be inside our
body. It affects approximately 1 of every 10,000 Figure 4. Myasthenia gravis reduces the effciency of neuromuscular transmission.
people. The hallmark of the disorder, which was Electromyographs (EMGs) show muscle responses elicited by stimulating motor nerves. In
originally described by the British physician Thomas typical individuals, each stimulus in a train evokes the same contractile response. In patients
Willis in 1685, is muscle weakness, particularly during with myasthenia gravis, transmission rapidly fatigues, although it can be partially restored
sustained activity (Figure). Although the course is by administration of AChE inhibitors such as neostigmine.

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variable, myasthenia commonly affects muscles controlling the eyelids (resulting in drooping of the eyelids, or ptosis) and eye
movements (resulting in double vision, or diplopia). Muscles controlling facial expression, chewing, swallowing, and speaking
are other common targets.

Another example of the involvement of Ach in pathology is Alzheimer’s disease. In this neurodegenerative disorder,
cholinergic neurons are affected more than others. Loss of these neurons impairs synaptic plasticity leading to memory
impairment.
Glutamate is the most important excitatory
NTM in the human brain and it is estimated that more
than half of all brain synapses release this
neurotransmitter. In stroke, epilepsy, brain trauma,
seizures, Alzheimer’s disease there is an excessive
release of glutamate that can produce excitotoxic brain
damage. There are several types of ionotropic glutamate
receptors (see Figure 5). AMPA receptors, NMDA
receptors, and kainate receptors are named after the
agonists that activate them: AMPA (α-amino-3-
hydroxyl-5-methyl-4-isoxazole-propionate), NMDA
(N-methyl-d-aspartate), and kainic acid. All of these
receptors are glutamate-gated cation channels that allow
the passage of Na+ and K+, similar to the nAChR. Hence
AMPA, kainate, and NMDA receptor activation always
produces excitatory postsynaptic responses. Most
central excitatory synapses possess both AMPA and
NMDA receptors. Antagonist drugs that selectively
block either AMPA or NMDA receptors are often used
to identify synaptic responses mediated by each receptor Figure 5. Glutamatergic synapse. While essential for synaptic plasticity and
long term potentiation, excessory activation of ionotropic glutamate receptors
type. Such experiments reveal that excitatory may lead to cell injury and death.
postsynaptic currents (EPSCs) produced by NMDA
receptors are slower and last longer than those produced by
AMPA receptors. EPSCs generated by AMPA receptors
usually are much larger than those produced by other types of
ionotropic glutamate receptors, so that AMPA receptors are
the primary mediators of excitatory transmission in the brain.
The physiological roles of kainate receptors are less well
defined; in some cases, these receptors are found on
presynaptic terminals and serve as a feedback mechanism for
glutamate release. NMDA receptors have physiological
properties that set them apart from the other ionotropic
glutamate receptors. Perhaps most significant is that the pore
of the NMDA receptor channel allows the entry of Ca 2+ in
addition to Na+ and K+. As a result, excitatory postsynaptic
potentials (EPSPs) produced by NMDA receptors increase
the concentration of Ca2+ in the postsynaptic neuron, with
Ca2+ then acting as a second messenger to activate
intracellular signaling processes. Another key property is that
Mg2+ blocks the pore of this channel at hyperpolarized
membrane potentials, while depolarization pushes Mg2+ out
of the pore. This imparts a peculiar voltage dependence to
current flow through the receptor; removing extracellular
Mg2+ eliminates this behavior, which demonstrates that Mg2+
confers the voltage dependence. Because of this property,
NMDA receptors pass cations (most notably Ca2+) only when
the postsynaptic membrane potential is depolarized, such as
during activation of strong excitatory inputs and/or during
action potential firing in the postsynaptic cell. This

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requirement for the coincident presence of both glutamate and postsynaptic depolarization to open NMDA receptors is
widely thought to underlie some forms of synaptic information storage, such as long-term synaptic plasticity. Another
unusual feature of NMDA receptors is that their gating requires a co-agonist—the amino acid glycine, which is present in
the ambient extracellular environment of the brain.
Based on this features one may consider NMDA
as an ionotropic receptor with metabotropic features. But
glutamatergic synapses also have several types of
metabotropic receptors as well (mGluRs).
There are five well-established biogenic amine
neurotransmitters: the three catecholamines—dopamine,
norepinephrine (noradrenaline), and epinephrine
(adrenaline)—and histamine and serotonin.
Dopamine is present in several brain regions
(Figure 7,A), although the major dopamine-containing
area of the brain is the corpus striatum, which receives
major input from the substantia nigra and plays an
essential role in the coordination of body movements. In
Parkinson’s disease, for instance, the dopaminergic
neurons of the substantia nigra degenerate, leading to a
characteristic motor dysfunction. Dopamine is also
believed to be involved in motivation, reward, and
reinforcement; many drugs of abuse work by affecting
dopaminergic circuitry in the CNS. Dopamine was
similarly shown to be involved in other types of addiction,
including alcohol and smartphone addiction. In addition
to these roles in the CNS, dopamine also plays a poorly
understood role in some sympathetic ganglia. Dopamine
Once released, dopamine acts exclusively by activating
G-protein-coupled receptors. Most dopamine receptor
subtypes act by either activating or inhibiting adenylyl
cyclase. Activation of these receptors generally
contributes to complex behaviors; for example,
administration of dopamine receptor agonists causes
hyperactivity and repetitive, stereotyped behavior in
laboratory animals. Dopamine is involved in nausea and
vomiting by its effect on medulla oblongata. Dopamine
receptor antagonists can also elicit catalepsy, a state in
which it is difficult to initiate voluntary motor movement,
suggesting a basis for this aspect of some psychoses.
Norepinephrine is used as a neurotransmitter in
the locus coeruleus (Fig. 7, B), a brainstem nucleus that
projects diffusely to a variety of forebrain targets and
influences stress response, sleep and wakefulness,
arousal, attention, and feeding behavior. Perhaps the most
prominent noradrenergic neurons are sympathetic
ganglion cells, which employ norepinephrine as the major
peripheral transmitter in this division of the visceral
motor system.
Epinephrine (also called adrenaline) is found in
the brain at lower levels than the other catecholamines
and also is present in fewer brain neurons than other
catecholamines. Epinephrine-containing neurons in the
CNS are primarily in the lateral tegmental system and in Figure 7. The distribution of catecholamine neurotransmitters in the human
the medulla and project to the hypothalamus and thalamus brain. Shown are neurons and their projections (arrows) that contain
catecholamine neurotransmitters. Curved arrows along the perimeter of the
(Figure 7,C). These epinephrine-secreting neurons cortex indicate the innervation of lateral cortical regions not shown in this
regulate respiration and cardiac function. midsagittal plane of section.

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 Histamine is found in neurons in the
hypothalamus that send sparse but widespread
projections to almost all
regions of the brain and spinal cord (Figure 8A).
The central histamine projections mediate arousal
and attention, similar to central Ach and
norepinephrine projections. Histamine also
controls the reactivity of the vestibular system.
Allergic reactions or tissue damage cause release
of histamine from mast cells in the bloodstream.
The close proximity of mast cells to blood vessels,
together with the potent actions of histamine on
blood vessels, raises the possibility that histamine
may influence brain blood flow.
Serotonin, or 5-hydroxytryptamine (5-
HT), was initially thought to increase vascular
tone by virtue of its presence in blood serum
(hence the name serotonin). Serotonin is found
primarily in groups of neurons in the raphe region
of the pons and upper brainstem, which have
widespread projections to the forebrain (Figure
8B) and regulate sleep and wakefulness. 5-HT
occupies a place of prominence in
neuropharmacology because a
large number of antipsychotic drugs that are
valuable in the treatment of depression and
anxiety act on serotonergic pathways. It was
shown, that the levels of serotonin are decreased
in depression. Many antidepressant drugs (e.g.
Prozac) are selective serotonin reuptake inhibitors
(SSRIs) that inhibit transport of 5-HT by specific
serotonin transporter SERT.
A large number of 5-HT receptors have
been identified. Most 5-HT receptors are
metabotropic, with a monomeric structure typical
of G-protein-coupled receptors. Metabotropic 5-
HT receptors have been implicated in a wide
range of behaviors, including circadian rhythms,
motor behaviors, emotional states, and state of
mental arousal. Impairments in the function of
these receptors have been implicated in numerous
psychiatric disorders, such as depression, anxiety
disorders, and schizophrenia, and drugs acting on
serotonin receptors are effective treatments for Figure 8. The distribution of histamine and serotonin neurotransmitters in the human
several of these conditions. The psychedelic drug brain. Diagrams show the distribution of neurons and their projections (arrows)
LSD (lysergic acid diethylamide) presumably containing histamine (A) or serotonin (B). Curved arrows along the perimeter of the
causes hallucinations by activating multiple types cortex indicate the innervation of lateral cortical regions not shown in this midsagittal
plane of section.
of metabotropic 5-HT receptors. Activation of 5-
HT receptors also mediates satiety and decreased
food consumption, which is why serotonergic drugs are sometimes useful in treating eating disorders.
Another group of serotonin receptors, the 5-HT3 receptors, are ligand-gated ion channels formed from
combinations of the five 5-HT 3 subunits. 5-HT3 receptors are nonselective cation channels and therefore mediate excitatory
postsynaptic responses. Ligand-binding sites reside within the extracellular domains of these receptors and serve as targets
for a wide variety of therapeutic drugs, including ondansetron (Zofran) and granisetron (Kytril), which are used to prevent
postoperative nausea and chemotherapy-induced emesis.

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 GABA and Glycine
Most inhibitory synapses in the brain and spinal cord use either γ-aminobutyric acid (GABA) or glycine as
neurotransmitters, correspondingly. The enzyme glutamic acid decarboxylase (GAD), which is found almost exclusively in
GABAergic neurons, catalyzes the conversion of glutamate to GABA. GAD requires a co-factor, pyridoxal phosphate, for
activity. Because pyridoxal phosphate is derived from vitamin B6, a deficiency of this vitamin can lead to diminished GABA
synthesis. The significance of this fact became clear after a disastrous series of infant deaths were linked to the omission of
vitamin B6 from infant formula. The absence of vitamin B6 greatly reduced the GABA content of the brain, and the
subsequent loss of synaptic inhibition caused seizures that in some cases were fatal.
GABAergic synapses employ two types of postsynaptic receptors, called GABAA and GABAB. GABAA are
ionotropic receptors, while GABAB are metabotropic receptors. The ionotropic GABAA receptors are GABA-gated anion
channels, with Cl– being the main permeant ion under physiological conditions. The reversal potential for Cl– usually is
more negative than the threshold for action potential firing due to the action of the K +/Cl– co-transporter, which keeps
intracellular Cl– concentration low. Thus, activation of these GABA receptors causes an influx of negatively charged Cl –
that inhibits postsynaptic cells. In cases where postsynaptic Cl- concentration is high — in developing neurons, for example
— GABAA receptors can excite their postsynaptic targets.

Unconventional Neurotransmitters
In addition to the conventional neurotransmitters already described, some unusual molecules are used for signaling between
neurons and their targets. These chemical signals can be considered as neurotransmitters because of their roles in
interneuronal signaling and because their release from neurons is regulated by Ca 2+. However, they are unconventional in
comparison with other neurotransmitters because they are not stored in synaptic vesicles and are not released from
presynaptic terminals via exocytotic mechanisms. In fact, these unconventional neurotransmitters need not be released from
presynaptic terminals at all and are often associated with retrograde signaling (that is, from postsynaptic cells back to
presynaptic terminals).
• Endocannabinoids are a family of related endogenous signals that interact with cannabinoid receptors. These receptors are
the molecular targets of ∆9-tetrahydrocannabinol, the psychoactive component of the marijuana plant, Cannabis sattiva.
While some members of this emerging group of chemical signals remain to be determined, anandamide and 2-
arachidonoylglycerol (2-AG) have been established as endocannabinoids. These signals are unsaturated fatty acids with
polar head groups and are produced by enzymatic degradation of membrane lipids. Production of endocannabinoids is
stimulated by a second messenger within postsynaptic neurons, typically a rise in postsynaptic Ca2+ concentration, allowing
these hydrophobic signals to diffuse through the postsynaptic membrane to reach cannabinoid receptors on other nearby
cells. Endocannabinoid action is terminated by carrier-mediated transport of these signals back into the postsynaptic neuron, where
they are hydrolyzed by the enzyme fatty acid hydrolase. At least two types of cannabinoid receptors have been identified, with most
actions of endocannabinoids in the CNS mediated by the CB1 type. The CB1 receptor is a G-protein-coupled receptor related to the
metabotropic receptors for ACh, glutamate, and other conventional neurotransmitters. Several compounds that are structurally related
to endocannabinoids and that bind to the CB1 receptor have been synthesized. These compounds act as agonists or antagonists of the
CB1 receptor and serve both as tools for elucidating the physiological functions of endocannabinoids and as targets for developing
therapeutically useful drugs. Endocannabinoids participate in several forms of synaptic regulation. The best-documented action of these
agents is the inhibition of communication between presynaptic inputs and their postsynaptic target cells. In both the hippocampus and
the cerebellum (among other brain regions), endocannabinoids serve as retrograde signals that regulate GABA release at certain
inhibitory synapses. At such synapses, depolarization of the postsynaptic neuron causes a transient reduction in inhibitory postsynaptic
responses. Depolarization reduces synaptic transmission by elevating the concentration of Ca 2+ in the postsynaptic neuron; this rise in
Ca2+ triggers synthesis and release of endocannabinoids from the postsynaptic cells. The endocannabinoids then bind to CB1 receptors
on presynaptic terminals, inhibiting the amount of GABA released in response to presynaptic action potentials, and thereby reducing
inhibitory transmission. The mechanisms responsible for the reduction in GABA release are not entirely clear but probably involve
effects on voltage-gated Ca2+ channels and/or K+ channels in the presynaptic neurons.
• Nitric oxide (NO) is an unusual and especially interesting chemical signal. It is a gas produced by the action of nitric oxide synthase,
an enzyme that converts the amino acid arginine into a metabolite (citrulline) and simultaneously generates NO. Within neurons, NO
synthase is regulated by Ca2+ binding to the Ca2+ sensor protein calmodulin. Once produced, NO can permeate the plasma membrane,
meaning that NO generated inside one cell can travel through the extracellular medium and act inside nearby cells. Thus, this gaseous
signal has a range of influence that extends well beyond the cell of origin, diffusing a few tens of micrometers from its site of production
before it is degraded. This property makes NO a potentially useful agent for coordinating the activities of multiple cells in a localized
region and may mediate certain forms of synaptic plasticity that spread within small networks of neurons․