Biochemistry of Neurotransmitters

NEUROCHEMICAL TRANSMISSION :

1-Neurons communicate with other cells by the release of chemical

neurotransmitter that act transiently on post synaptic receptors, then
removed from synaptic cleft .

2-A neurotransmitter is stored in synaptic vesicles and released on nerve

stimulation by exocytosis following the opening of voltage- gated Ca+2 ion
channels in the nerve terminal .

3-Once released , a neurotransmitter binds to and stimulate its receptors

briefly before being rapidly removed from the synapse , thereby allowing the
transmission of a new neuronal message .

4- Other removal mechanisms include enzymatic degradation into a non active

Metabolite in the synapse or diffusion away from the synapse into
extracellular space .

CLASSES OF NEUROTRANSMITTERS
Neurotransmitters fall into 3 main classes :

(A) Amino acids : Examples of this class include :

1- Excitatory amino acids e.g. Glutamate , Aspartate .

 2- Inhibitory amino acids e.g. Glycine , Gamma amino butyric acid

3- (GABA ) , this compound is biosynthetically a monoamine but it has the

features of amino acids transmitters, not a monoaminergic one.

(B) Monoamines (Biogenic amines ):

They are synthesized from single readily available amino acid precursor.

e.g Acetyl choline(Ach) –Dopamine (DA) – Epinephrine (EPI) –Norepinephrine

(NE) and Serotonin or 5-hydroxy tryptamine (5HT) .

( C ) Polypeptides (Neuropeptides ) :

Neuropeptide consists of amino acid side chain varying from 3 to several

dozen . Examples are : Opioids and substance P.

 Recently , a novel set of neurotransmitters has been identified as

membrane – soluble molecules that may act as both anterograde &
retrograde signaling molecules between neurons . Examples include

Nitric oxide and Arachidonic acid

GENERAL FUNCTIONS OF NEUROTRANSMITTERS

Neurotransmitter Function
1- Dopamine Affect , reward , control of movement.
2- Norepinephrine Affect , alertness .
3- Serotonin Mood , arousal , modulation of pain .
4- Acetyl Choline Control of movement , cognition
5- GABA General inhibition
6- Glycine General inhibition
7- Glutamate General excitation , sensation
8- Substance P Transmission of pain
9- Opioid peptides Control of pain
10- Nitric oxide Vasodilation ,metabolic signaling

We shall discuss now the role of each of the previous neurotransmitters from
the biochemical point of view .

(1) Acetyl Choline (ACh )

(a) Neurons using acetylcholine as their neurotransmitter are called
cholinergic neurons .

(b) Acetyl choline (Ach) is synthesized in the cholinergic neuron from choline

And acetate by the action of the enzyme choline acetyl transferase that is

Localized in the cytoplasm of cholinergic neurons and is an identifyin

Marker of cholinergic neuron .

(c )The enzyme acetyl choline esterase(AChE ) hydrolyzes ACh back to choline

And acetate after the release of Ach , it is present in all parts of synaptic

Cell membrane allowing rapid & efficient hydrolysis of extracellular Ach .

(d)The choline generated from ACh hydrolysisis taken up by cholinergic

Neuron to ensure a steady supply of the precursor for ACh synthesis .

(2) Catecholamines
(a) Catecholamines consist of a phenyl ring with two hydroxyl groups and an

Ethylamine side chain . All catecholamines : Dopamine (DA), norepinephrine

(NE) and epinephrine share a common pathway for enzymatic biosynthesis .

(b) Three of the enzymes involved , tyrosine hydroxylase (TH) , dopamine

Hydroxylase (DBH) and phenylethanolamine N-methyl transferase (PNMT)

are unique to catecholamine secreting cells and are all derived From a
common gene.

(c ) Dopaminergic neurons express only TH , noradrenergic neurons express

Both TH & DBH while epinephrine -secreting cells express all three .

(d)The rate-limiting enzyme in catecholamine biosynthesis is tyrosine

Hydroxylase that converts L-tyrosine to L – 3,4 dihydroxy phenyl alanine

(L- Dopa).

(e)A non-specific cytoplasmic enzyme called aromatic L- amino acid

Decarboxylase catalyzes the decarboxylation of L- dopa to dopamine,

Which in turn is taken up in storage vesicles and is protected from

The enzymatic attack .

(f) In NE and EPI synthenthesizing neurons , the enzyme DBH which converts

DA into NE is found within vesicles , unlike other synthetic enzymes that

Are found in the cytoplasm .

(g) In EPI secreting cells , PNMT is localized in the cytoplasm , this enzyme

Adds a methyl group to the amine in NE to produce EPI .

(h) Two enzymes are involved in the degradation of catecholamines following

 Exocytosis , Monoamine oxidase(MAO) removes the amin group & catechol-

Amine – Omethyltransferase (COMT) methylates the 3rd OH group .

(3)Serotonin

(a) Serotonin or 5- hydroxytryptamine (5HT) is the neurotransmitter in seroton-

-ergic neurons , chemical transmission in these neurons in similar ways to

That in catecholaminergic neurons .

(b) Tryptophan hydroxylase (TH) , a marker of serotonergic neurons , converts

tryptophan first into 5- hydroxytryptophan (5-HTP) , which is thenconverted
by decarboxylation into 5-hydroxy tryptamine (5-HT)or serotonin.

(4)Glutamate & Aspatate

(a) Both glutamate &aspartate amino acids serve as excitatory transmitters of

The CNS. They are important substrates for transamination reactions in all cells

(c) In certain neurons , these amino acids serve as neurotransmitters, stimulate

Specific receptors in the synapse .

(d) Since glutamate & aspartate are readily interconvertible in transamination

reactions in cells , including neurons , it was difficult to distinguish between

Neurons that use glutamate as a transmitter from those using aspartate and
more over both amino acids stimulate common receptors ,therefore it is
better to refer to both as glutamatergic neurons .
 (5)Aminobutyric aid &Glycine
(a) The inhibitory amino acid transmitters GABA & Glycine bind to their
respective receptors , causing hyperpolarization of the postsynaptic
membrane .

(b) GABAergic neurons represent the major inhibitory neurons of the CNS

Whereas glycinergic neurons are found in only limited numbers and

Are restricted to the spinal cord & brain stem .

(c ) It should be noticed that GABA is synthesized in neurons by glutamate

Decarboxylase which is a marker of GABAergic neurons . Glycinergic

Transmission is not well characterized as GABAergic one .

(6)Neuropeptides
(a)Neurally active peptides are stored in synaptic vesicles and undergo
exocyotic release in common with other neurotransmitters.

(b)The most important neuropeptides are :

(1) Opoids : Met-enkephalin – leuenkephalin – Dynorphin – Endorphin

(2)Gastrointestinal peptides : Cholecystokinin – Substance P- Vasoactive

intestinal.

(3)Hypothalamic & Pituitary peptides : Thyrotropin –releasing hormone TRH

Somatostatin – Luteinizing hormone releasing ormone LHRH – Vasopressin

And Oxytocin .

7-Nitric Acid & Arachidonic acid

 (1) Nitric oxide :

(a)It is a labile free-radical gas that is synthesized on demand from its

precursor L- arginineby nitric oxide synthase (NOS) .

(b)Because NOS activity is regulated by Ca+2 , the release of NO is calcium

– dependent . It was first discovered in Macrophages and allowed them
to kill tumor cells .

(2)Arachidonic acid : (a) A fatty acid that is released from phospholipids ,