Neurotransmitters

Neurotransmitters are endogenous chemicals that

transmit signals across a synapse from one neuron (nerve

cell)to another 'target' neuron.

Synapses are the junctions where neurons release a

chemical neurotransmitter that acts on a postsynaptic

target cell, which can be another neuron or a muscle or

gland cell

Neuromodulators are chemicals released by neurons

have little or no direct effects on their own but can modify

the effects of neurotransmitters.

Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. The histological examinations by Ramón y Cajal (1852–1934), a 20 to 40nm 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. In 1921 German pharmacologist Otto Loewi (1873–1961) confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs.

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There are four main criteria for identifying

neurotransmitters:

1. The chemical must be synthesized in the neuron or

otherwise be present in it.

2. When the neuron is active, the chemical must be released

and produce a response in some target.

3. The same response must be obtained when the chemical is

experimentally placed on the target.

4. A mechanism must exist for removing the chemical from

its site of activation after its work is done.

IDENTIFICATION

Amino acids: glutamate, aspartate, D-serine,

γ-aminobutyric acid, glycine.

Monoamines: dopamine, Norepinephrine,

Epinephrine, histamine, serotonin.

Trace amines:

phenethylamine, tyramine, 3-iodothyronamine,

octopamine, tryptamine.

Peptides: somatostatin, substance P, cocaine

and amphetamine regulated transcript, opioid

peptides.

Gasotransmitters: nitric oxide (NO), carbon

monoxide (CO), hydrogen sulfide (H2S)

Others: acetylcholine (ACh), adenosine,

Anandamide.

Reuptake• From the synaptic cleft back into the cytoplasm of the

neuron

The reuptake systems employ two families of transporter proteins:

They include transporters for Norepinephrine, dopamine, serotonin, GABA, and glycine, as well as transporters for proline, taurine, and the acetylcholine precursor choline. In addition, there may be an epinephrine transporter.

The other family is made up of at least three transporters that mediate glutamate uptake by neurons and two that transport glutamate into astrocytes.

VMAT1 & VMAT2:

Both have a broad specificity, moving

dopamine, Norepinephrine,

epinephrine, serotonin, and

histamine from the cytoplasm into

secretory granules.

• There is also a vesicular GABA transporter (VGAT) that moves GABA

and glycine into vesicles and a

vesicular acetylcholine transporter.

2-acetoxy-N,N,Ntrimethylethanaminium

Structure:

Acetylcholine was the first neurotransmitter to be discovered.Isolated in 1921 by a German biologist named Otto Laewi.Precursor: cholineActs on: nicotinic receptors and muscarnic receptors Inactivated by acetyl choline esterase enzyme or reuptake by vesicular acetyl choline transferase (VAchT)

Vasodilation, cardiac inhibition, GI peristalsis; control of thought, mood, sleep, muscles, bladder, sweat glands

There are three Catecholamines :

1.Dopamine 2.Epinephrine3.Norepinephrine

Precursor : Tyrosine (amino acid)

Synthesis site : Adrenal medulla

Acts on alpha (α) and beta (β)

adrenergic receptors

Inactivation is done by MAO and by

catechol-O-methyl transferase (COMT)

α & β Receptors

• Epinephrine and Norepinephrine both act on α and β receptors, with norepinephrine having a greater affinity for α-adrenergic receptors and epinephrine for β-adrenergic receptors.

Synthesized from the amino acid tyrosine.

Generally involved in regulatory motor activity, in

mood, motivation and attention.

Functions :

1. Induction of vomiting

2. Inhibition of prolactin secretion

3. Stimulation of GnRH

4. Schizophrenia

5. Control of movements(parkinsonism)

Schizophrenics have too much dopamine.

Patients with Parkinson's Disease have too little

Five different dopamine receptors (D1, D2,

D3, D4, D5) are known and exist in multiple

forms.

Most, but perhaps not all, of the responses

to these receptors are mediated by

heterotrimeric G proteins.

Overstimulation of D2 receptors is thought to

be related to schizophrenia.

D3 receptors are highly localized, especially

to the nucleus accumbens

Dopamine Receptors

SerotoninAlso known as 5-hydroxy tryptamine

Precursor : Tryptophan

It is found within the brain stem in the

midline Raphé nuclei,

It is present in highest concentration in

blood platelets and in the gastrointestinal

tract

It is inactivated by the action of the MAO

which converts it into

5-hydroxyindoleacetic acid

Serotonergic Receptors• 5-HT

1 - 5-HT

7receptors

• Most of these are G protein-coupled receptors

• 5-HT1

=> 5-HT1A

, 5-HT1B

, 5-HT1D

, 5-HT1E

, & 5-HT1F

• 5-HT2

=> 5-HT2A

, 5-HT2B

, & 5-HT2C

• 5-HT2A

-platelet aggregation and smooth muscle

contraction.

• 5-HT3

-ligand-gated ion channels present in the GIT

are related to vomiting.

• 5-HT4

-in the GIT, where they facilitate secretion

and peristalsis.

• 5-HT5

=> 5-HT5A

& 5-HT5B

• 5-HT6

& 5-HT7-distributed throughout the limbic

system

(γ-amino butyric acid)Major inhibitory mediator in the brain, including being

responsible for presynaptic inhibition.

Precursor : glutamate

Reuptake by vesicular GABA transferase

Metabolized primarily by transamination to succinic

semialdehyde

GABA transaminase (GABA-T) catalyzes the

transamination.

Three subtypes of GABA receptors have been identified: GABAA, GABAB, and GABAC

The GABAA and GABAC receptors are ion channels made up of five subunits surrounding a pore . In this case, the ion is Cl– . The GABAB receptors are metabotropic,coupled to heterotrimeric G proteins that increase conductance in K+ channels, inhibit adenylyl cyclase, and inhibit Ca2+ influx.

GABA Receptors

Peptides that bind to opioid receptors are

called opioid peptides.

The ENKEPHALINS are found in nerve endings

in the gastrointestinal tract and many different

parts of the brain, and they appear to function

as synaptic transmitters.

They have analgesic activity when injected

into the brain stem.

They also decrease intestinal motility.

RECEPTORS

µ , κ , δ

All three are G protein-coupled

receptors, and all inhibit adenylyl cyclase.

Activation of µ receptors increases K+

conductance, hyperpolarizing central

neurons and primary afferents.

Activation of κ and δ receptors closes

Ca2+

channels.

General mechanism of action

Acetylcholine esterase