Type of neurotransmitter, Synthesis-Activation-Termination and

Comparison between normal and Disorder.

Noneuronsrundirectlyfromtheperipherytothebrain.Normallytheinitiatedsignalisrelayedbyseveral
intermediateneuralcells.Theinterconnectionbetweenneurons,calledthesynapse,behavesasasimpleswitchbutalso
hasaspecialroleininformationprocessing.Thejunction(synapse)betweenaneuralcellandthemusclethatit
innervates,calledtheneuromuscularjunction,hasbeenparticularlywellstudiedandprovidesmuchofourquantitative
understandingaboutsynapses.Sinceitisimpossibletodiscussthestructureofthenervoussystemwithoutincluding
synapses.
Thefunctionofthesynapseistotransferelectricactivity(information)fromonecelltoanother.Thetransfer
canbefromnervetonerve(neuroneuro),ornervetomuscle(neuromyo).Theregionbetweenthepreand
postsynapticmembraneisverynarrow,only3050nm.Itiscalledthesynapticcleft(orsynapticgap).Direct
electric communication between pre and postjunctional cells does not take place; instead, a chemical
mediatorisutilized.Thesequenceofeventsisasfollows:

1. Anactionpulsereachestheterminalendingsofthepresynapticcell.

2. A neurotransmitter is released, which diffuses across the synaptic gap to bind to receptors in
specializedmembranesofthepostsynapticcell.

3. Thetransmitteracts toopenchannels ofoneorseveralionspecies,resulting inachangeinthe

transmembrane potential. If depolarizing, it is an excitatory postsynaptic potential (EPSP); if
hyperpolarizing,aninhibitorypostsynapticpotential(IPSP).

Different Types of Synapses:

The human nervous system uses a number of different neurotransmitter and neuroreceptors, and they
dont all work in the same way. We can group synapses into 4 types:
1. Excitatory Ion Channel Synapses.
These synapses have neuroreceptors that are sodium channels. When the channels open, positive ions flow
in, causing a local depolarisation and making an action potential more likely. This was the kind of synapse
described above. Typical neurotransmitters are acetylcholine, glutamate or aspartate.
2. Inhibitory Ion Channel Synapses.
These synapses have neuroreceptors that are chloride channels. When the channels open, negative ions
flow in causing a local hyperpolarisation and making an action potential less likely. So with these synapses
an impulse in one neurone can inhibit an impulse in the next. Typical neurotransmitters are glycine or
GABA.
3. Neuromuscular Junctions.
These are the synapses formed between motor neurones and muscle cells. They always use the
neurotransmitter acetylcholine, and are always excitatory. We shall look at these when we do muscles.
Motor neurones also form specialised synapses with secretory cells.
5. Electrical Synapses.
In these synapses the membranes of the two cells actually touch, and they share proteins. This allows the
action potential to pass directly from one membrane to the next. They are very fast, but are quite rare,
found only in the heart and the eye.

What are Neurotransmitters?

Neurotransmitter is a chemical substance which is released at the end of a nerve fibre by the arrival of a nerve
impulse and, by diffusing across the synapse or junction, effects the transfer of the impulse to another nerve
fibre, a muscle fibre, or some other structure.

Name a few Neurotransmitters:

There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides,
and monoamines is sufficient for some classification purposes.
 Types of Neurotransmitters
1. Neurotransmitters can be classified by function:
Excitatory neurotransmitters: These types of neurotransmitters have excitatory effects on the neuron;
they increase the likelihood that the neuron will fire an action potential. Some of the major excitatory
neurotransmitters include epinephrine and norepinephrine.
Inhibitory neurotransmitters: These types of neurotransmitters have inhibitory effects on the neuron;
they decrease the likelihood that the neuron will fire an action potential. Some of the major inhibitory
neurotransmitters include serotonin and GABA

Some neurotransmitters, such as acetylcholine and dopamine, can both excitatory and inhibitory effects
depending upon the type of receptors that are present.

2. Neurotransmitters can also be classified as :

Small Molecule: Amino Acids and Amines
Large Molecule: Peptides

So What Function do these Neurotransmitters perform??

1. ENDORPHINS (Opiods): Mood elevating, enhancing, euphoric. The more present, the happier you
are! Natural pain killers.
2. NOREPINEPHRINE: Excitatory, feel happy, alert, motivated. Anti-depressant, appetite control,
energy, sexual arousal.
3. DOPAMINE: Feelings of bliss and pleasure, euphoric, appetite control, controlled motor movements,
feel focused.
4. ACETYLCHOLINE: Alertness, memory, sexual performance, appetite control, release of growth
hormone.
5. PHENYLETHYLMINE (PEA): Feelings of bliss, involved in feelings of infatuation (high levels
found in chocolate).
6. ENKEPHALINS: Restrict transmission of pain, reduce craving, reduce depression.
7. GABA (Gamma Amino Butyric Acid): Found throughout central nervous system, anti-stress, anti-
anxiety, anti-panic, anti-pain; Feel calm, maintain control, focus.
8. SEROTONIN: Promotes and improves sleep, improves self esteem, relieves depression, diminishes
craving, prevents agitated depression and worrying.
9. MELATONIN: "Rest and recuperation" and "anti-aging" hormone. Regulates body clock.
10. OXYTOCIN: Stimulated by Dopamine. Promotes sexu+al arousal, feelings of emotional attachment,
desire to cuddle.

Neurotransmitters are synthesized, transported and packaged in slightly different ways

depending upon whether they are small molecule neurotransmitters or neuropeptides.
Small molecule neurotransmitters are synthesized by cytosolic proteins which are slowly
transported to the terminal. In the terminal, synthesis of the neurotransmitter occurs.
With the large neuropeptides, synthesis of precursor proteins occurs in the soma, and then
the neuropeptides are packaged. The vesicles undergo fast anterograde transport and while
in transport, the large precursor proteins are cleaved to form the neuropeptides.
So while small molecule neurotransmitters are synthesized in the terminals, neuropeptides
are synthesized partly in the soma and partly during transport.
AMINO ACIDS:
SYNTHESIS OF GABA

Huntington chorea:
A degenerative disease characterized by involuntary movements secondary to the loss of
GABA producing neurons in the caudate and putamen.
Decreased GABA- containing striatonigral (straitum to substantia nigra) projections result
in a lower GABA levels to the substantia nigra.
Parkinsonism:
A reduction in GABA causes an elevation of the ratio of dopamine to acetylcholine, which
produces abnormal movements.
A lower ratio of dopamine to acetycholine , resulting from loss of nigral dopaminergic
cells, is associated with the reduced movement (bradykinesia) or lack of movements of
Parkinsonism.

SYNTHESIS OF GLUTAMATE

Especially important to memory.

It is actually toxic to neurons and an excess will kill them.
Sometimes brain damage or a stroke will lead to an excess and end with many more
brain cells dying than from the original trauma.
GLUTAMINASE
GLUTAMINE GLUTAMATE
 Aminotransferse
Amyotrophic Lateral Sclerosis results from excessive Glutamate production.

SYNTHESIS OF GLYCINE

Binds to a receptor which makes the post-synaptic membrane more permeable .

Glycine is an inhibitory NT.
Strychnine is a glycine antagonist which can bind to the glycine receptor without opening
the chloride ion channel (i.e. it inhibits inhibition). The resultant spinal hyper excitability
makes strychnine a poison.
Clinically mutation of glycine producing enzymes causes hyperglycemia, lethargy, seizures
and MR.

Clinically, mutation of glycine produces enzymes causing hyperglycemia, lethargy,

seizures and mental retardation
AMINES:
ACETYLCHOLINE
Voluntary movement of the muscles, including the muscles of the gastro-intestinal system.
Found in sensory neurons
Autonomic nervous system
Scheduling dream sleep (REM-Rapid Eye Movement).
The well-known poison botulin works by blocking acetylcholine, causing paralysis.
There is 90% loss of acetylcholine in the brains of people suffering from the Alzheimers
disease.

There is a reduction in the number of ACh-receptors in patients with MG which affects

transmission of nerve impulses to muscles of eyes, arms, hands, fingers, mouth, and
respiratory system.
Patients with MG form abnormal immune blood proteins (antibodies) against the ACh-
receptor. The antibody binds to the ACh-receptor instead of the neurotransmitter.
Production of these ACh-receptor antibodies believed to be by the Thymus gland (this gland
is normally active in infancy and supposed to be non-functional in adulthood)
Principle of drug therapy:
Anticholinesterase drugs Prolong the effect of the ACh that signals the muscles to act
ACh in Adults with Down Syndrome:
Some studies carried out on adults with Down syndrome have shown that there is significant
reduction in ChAT (choline acetyltransferase) the enzyme involved in ACh synthesis

DOPAMINE
Inhibitory NT
When it finds its way to its receptor sites, it blocks the tendency of that neuron to fire.
Strongly associated with reward mechanism in the brain. Drugs like cocaine, opium,
heroin and alcohol increase the levels of dopamine, as does nicotine.
 The main function of dopamine is co-ordination of body movements and emotional
arousal.
Involved in motivation, reward and reinforcement.
Schizophrenia has been shown to involve excessive amounts of dopamine in the
frontal lobes, and drugs that block dopamine are used to help schizophrenics.
Too little dopamine in the motor areas of the brain are responsible for Parkinsons
disease,
Uncontrollable muscle tremors
Dysarthric and stropping posture
Reduced movement.

Dopamine in Parkinsons disease:

Neurochemically, parkinsonism involves reduced levels of dopamine. Dopamine neurons in
the nigrostriatal pathway (one of the pathways through which dopamine acts) die.
Dopamine and ACh balance:
Dopamine and ACh neurotransmitters should normally be in balance. But in
parkinsonism, as the level of dopamine reduces, there is an excess of ACh.
Principle of drug therapy for Parkinsonism:
1. Drugs to increase dopamine (e.g Levadopa)
2. Drugs to diminish ACh (Anticholinergics like artane, cogentin)
Dopamine in normal ageing & Parkinsonism:
Dopamine levels fall in normal ageing
If it falls to 1/5th of its normal (original) value, then Parkinsonism is said to occur.
Dopamine in Schizophrenia:
Excessive dopamine activity has been reported in the mesolimbic pathway(VTA to nucleus
accumbens) of dopamine neurotransmitter.
Principle of drug therapy:
Thorazine and related drugs are that block dopamine receptors are used in the treatment of
schizophrenia.

NOR EPINEPHRINE
Associated with bringing nervous system into high alert.
Prevalent in the sympathetic nervous system
Increases our heart rate and blood pressure.
Maintains attention and forming memories.
Active projection of nor epinephrine in the forebrain is a key feature of awakeness-
arousal as distinguished from sleep.
Nor epinephrine projection to the basal nucleus of the forebrain is low in sleep and
virtually absent in REM (Rapid eye movement) sleep.
The basal nucleus when stimulated by nor epinephrine sends neuromodulating
acetylcholine to the cerebral cortex, thereby promoting alertness.

ADHD: increased levels of nor-epinephrine

EPINEPHRINE
The enzyme that synthesis epinephrine , phenylethanolamine- N-methyltransferase,
is also present only in epinephrine secreting neurons.
the metabolism of epinephrine is very similar to that of norepinephrine
 SERETONIN:
Acts on memory, emotions, wakefulness, sleep and temperature regulation.
Intimately involved in emotion and mood.
Too little serotonin leads to depression, problems with anger control, obsessive-
compulsive disorder and suicide.
It also leads to an increased appetite for carbohydrates (Starchy foods) and trouble
sleeping, which are also associated with depression and other emotional disorders.
It is also used in the treatment of autism.
It plays a role in perception.
Hallucinogens such as Lysergic Acid Diethylamide
(LSD) work by attaching to serotonin receptor sites and thereby blocking
transmissions in perceptual pathways.
 ACTIVATION OF NEUROTRANSMITTERS:
Neurotransmitters are formed in a presynaptic neuron and stored in small membrane-
bound sacks, called vesicles , inside this neuron. When this neuron is activated, these
intracellular vesicles fuse with the cell membrane and release their contents into the
synapse, a process called exocytosis.
Once the neurotransmitter is in the synapse, several events may occur.
(1)Diffuse across the synapse and bind to a receptor on the postsynaptic
membrane,
(2)Diffuse back to the presynaptic neuron and bind to a presynaptic receptor
causing modulation of neurotransmitter release
(3)Be chemically altered by an enzyme in the synapse, or
 (4)Be transported into a nearby cell.

Mechanism of Fast-Acting Neurotransmitters

Some neurotransmitters are referred to as fast-acting since their cellular effects occur
milliseconds after the neurotransmitter binds to its receptor. These neurotransmitters
exert direct control of ion channels by inducing a conformational change in the
receptor, creating a passage through which ions can flow. These receptors are often
called ligand -gated ion channels since the channel opens only when the ligand is
bound correctly. When the channel opens, it allows for ions to pass through from their
side of highest concentration to their side of lowest concentration. The net result
is depolarization if there is a net influx of positively charged ions orhyperpolarization if
there is a net inward movement of negatively charged ions. Depolarization results in a
continuation of the nerve impulse, whereas hyperpolarization makes it less likely that
the nerve impulse will continue to be transmitted.
The first ligand-gated ion channel whose structure and mechanism were studied in
detail was the nicotinic acetylcholine receptor of the neuromuscular junction. This
receptor contains five protein subunits, each of which spans the membrane four times.
When two acetylcholine molecules bind to this receptor, a channel opens, resulting in
sodium and potassium ions being transported at a rate of 10 7 per second.
Acetylcholine's action at these receptors is said to be excitatory due to the resulting
depolarization. Other receptors for fast transmitters have a similar amino acid
sequence and are believed to have a similar protein structure. Glycine and -
aminobutyric acid (GABA) also act on ligand-gated ion channels and are fast-acting.
However, they cause a net influx of chloride ions, resulting in hyperpolarization; thus,
their action is inhibitory.
Mechanism of Slow-Acting Neurotransmitters

Slower-acting neurotransmitters act by binding to proteins that are sometimes called G-

protein-coupled receptors (GPCRs). These receptors do not form ion channels upon
activation and have a very different architecture than the ion channels. However, the
timescale for activation is often relatively fast, on the order of seconds. The slightly
longer time frame than that for fast-acting neurotransmitters is necessary due to
additional molecular interactions that must occur for the postsynaptic cell to become
depolarized or hyperpolarized. The protein structure of a GPCR is one protein subunit
folded so that it transverses the membrane seven times. These receptors are referred
to as G-coupled protein receptors because they function through an interaction with
a GTP -binding protein, called G-protein for short.
The conformational change produced when a neurotransmitter binds to a GPCR causes
the G-protein to become activated. Once it becomes activated, the protein subunits
dissociate and diffuse along the intracellular membrane surface to open or close an ion
channel or to activate or inhibit an enzyme that will, in turn, produce a molecule called
a second messenger. Second messengers include cyclic AMP , cyclic GMP , and calcium
ions and phosphatidyl inositol. They serve to activate enzymes known as protein
kinases. Protein kinases in turn act to phosphorylate a variety of proteins within a cell,
possibly including ion channels. Protein phosphorylationis a common mechanism used
within a cell to activate or inhibit the function of various proteins.
Termination of Transmission
For proper control of neuronal signaling, there must be a means of terminating the
nerve impulse. In all cases, once the neurotransmitter dissociates from the receptor,
the signal ends. For a few neurotransmitters, there are enzymes in the synapse that
serve to chemically alter the neurotransmitter, making it nonfunctional. For instance,
the enzyme acetylcholinesterase hydrolyzes acetylcholine. Other neurotransmitters,
such as catecholamines and glutamate, undergo a process called reuptake. In this
process, the neurotransmitter is removed from the synapse via a transporter protein.
These proteins are located in presynaptic neurons or other nearby cells.
Causes of Neurotransmitter Imbalances :
Poor diet e.g., low protein, high sugar, high saturated fat, low unsaturated fat
Excess alcohol use/ drug use
Nutrient deficiencies
Certain medications
Chronic physical and emotional stress
Surgery/ operations
Medical conditions e.g., diabetes, thyroid conditions, cardiovascular diseases.
Restrictive diets
Genetic make up & individual biochemistry
Allergies
Chemical & food sensitivities
High stress and/or psychological trauma
Lack of sleep
Viruses & infections
Lack of, or excessive, exercise
Hormone imbalances
Essential fatty acid deficiencies
Blood sugar imbalances
Overly sedentary lifestyles

Metal toxicity
Digestive problems