MSc Medical Biochemistry,
Definition : - The chemical substance helpful for
signal transmission in central nervous system
&peripheral nervous system (via) the chemical
synapses is neurotransmitters.
Synaptic transmission is the predominant means by
which neurons communicate with each other.
The criteria for Chemical neurotransmitter
1) found in presynaptic axon terminal.
2) enzymes necessary for synthesis are present in
presynaptic neuron .
3) stimulation under physiological conditions results
4) mechanism exist for rapid termination of action.
5) direct application to postsynaptic terminal mimics
the activation of nerve stimulus.
6) drugs that modify metabolism of the
neurotransmitter should have predictable
physiological effects invivo assuming that the drug is
transported to the site where neurotransmitter acts.
Not all neuron to neuron transmission is by
neurotransmitters , gap junctions provides direct
neuron to neuron electrical conduction.
Neurotransmitter is stored in synaptic vesicle released
in response to nerve impulse & controled by calcium
Release of neurotransmitter is quantal event , that is a
nerve impulse reaching presynaptic terminal result in
release of transmitter from a fixed number of synaptic
Neurotransmitter action is terminated by metabolic
degradation , reuptake , or diffusion into other cell
Class :- 1 acetylcholine
Class : -2 The biogenic amines
norepinephrine , epinephrine
dopamine , serotonin .
Class : - 3 amino acids
gamma amino butyric acid (GABA) ,
glycine , glutamate , aspartate.
Class : - 4 nitric acid (NO)
carbonmonoxide ( co )
In addition to classical neurotransmitters many
neuropetides are identified as definite or probable
eg : - substance p , neurotensin , enkephalin , β –
endorphin , histamine,
vasoactive intestinal polypeptide,
cholecystokinin , neuropeptide Y
Neurotransmitters modulate the function of post
synaptic cells by binding to specific receptors of 2
1) ionotropic receptors ( direct ion channels that open
after binding of neurotransmitters. )
2) metabotropic receptors ( interact with G proteins
stimulating production of second messengers &
activating protein kinases , which modulate the
cellular events. )
G proteins couple several receptors to intra cellular
signaling system , linking neuronal excitability to
energy metabolism & second messenger systems.
G protein binding receptors include adenosine , Ach (
muscarnic ), norepinephrine , dopamine , serotonin
Kinetics of ionotropic receptors are fast , (< 1 ms ) ,
because neurotransmitters directly alter the electrical
property of the postsynaptic cell.
Kinetics of metabotropic receptors functions over
longer time periods.
This contributes to the potential for selective & finely
modulated signaling by neurotransmitters
The membrane of neuronal cell maintains an
asymmetry of inside outside voltage , & is electrically
Neuronal membranes are polarized to a potential of -
90 mV by the activity of Na+_k+ ATPase transport
Factors that control the neuroexcitability
1)voltage gated ion channels
2) neurotransmitter activated ion channels.
4)second messenger system.
The control of neuronal activity within normal limits
is by the modulation of excitatory & inhibotory events
Ligand gated channels are responsible for
communication between cells.
Voltage gated sodium channels are involved in
propagation of action potential , rapid activation is at
-60mV due to opening of fast transient channels.
Voltage gated potassium channels contribute to
repolarization ,this regulate repeated firing of action
potential by prolonging after spike repolarization.
Voltage dependent calcium channels trigger
neurotransmitter release , at rapid activation is around
Autoantibodies to ca++ channels in motor nerve
terminal leads to decreased release of Ach from nerve
terminal , this is seen in eaton lambert myasthenic
Voltage gated channels determine how inhibitory &
excitatory influences are integrated .
Acetyl choline is the neurotransmitter used by all
motor axons that arise from spinal cord, that is at
Junction consist of a single nerve terminal separated
from post synaptic region by synaptic cleft.
Motor end plate is the specialized portion of the
muscle membrane involved in the junction.
Junctional folds are prominent they contain high
density of Ach receptors.
Synthesis of Ach takes place in cytosol of nerve
choline acetyl transferase
acetyl coA+ choline Ach + coA
Ach is incorporated into membrane bound particle
called synaptic vesicles.
Assembly of synaptic vesicle with cell membrane
resembles assembly of transport vesicle involving
Release of Ach into synaptic cleft occurs by exocytosis ,
which involves fusion of vesicle with presynaptic
Nerve ending is depolarized by transmission of nerve
impulse this opens the voltage gated Ca++ channels ,
permitting influx of Ca++ from synaptic cleft to nerve
terminal , this Ca++ plays a role in exocytosis of Ach
Approximately 200 vesicles are released into synaptic
Each vesicle contains 10000 molecules of Ach.
Ach binds Ach receptor , receptor undergoes
conformational change opening the channel in the
receptor that allows entry of Na+, k+ resulting in
depolarization of muscle membrane.
Properties of Ach receptor of NMJ :
nicotinic receptor (nicotine is an agonist for the
a membrane glycoprotein containing 5 subunits. (
only α subunit binds Ach with high affinity.
2 molecules of Ach binds receptor to open the ion
channel which permits Na+ , K+ the receptor is thus
transmitter gated ion channel.
autoantibodies to receptors are implicated in causation
of myasthenia gravis
Snake venom α bungarotoxin binds tightly to the α
subunit & can used to label the receptor .
Formation of autoantibodies to Ach
receptors in NMJ
damage to receptors by autoantibodies
reduction in number of receptors
Episodic weekness of muscles supplied by cranial
When the channel closes Ach dissociates & it is
hydrolyzed by acetyl choline esterase.
acetyl choline esterase
Ach + H2O Acetate +choline
Choline is recycled into nerve terminal by active
transport , it can be used for synthesis of Ach.
The classical neurotransmitter of autonomic ganglia
whether sympathetic or parasympathic is acetyl
2 classes of receptors are present in autonomic nervous
1) nicotinic eceptors ,
2) muscarnic recptors.
Nicotinic receptors in autonomic ganglia are different
from those on skeletal muscle.
Nicotinc & muscarnic receptors mediate excitatory
postsynaptic potentials (EPSP) , but these potential
have different time course.
Stimulation of presynaptic neuron elicits a fast EPSP
followed by a slow EPSP.
Fast EPSP results from activation of nicotinic receptors
which cause of ion channels to open.
Slow EPSP is mediated by activation of muscarnic
receptors that inhibit the M current , a current that is
produced by K+ conductance.
Besides acetyl choline sympathetic preganglion
neurons may release enkephalin , substance p , LHRH ,
neurotensin or somatostatin.
Neurotransmitter in parasympathetic postganglionic
neurons is acetyl choline.
Actions are mediated by 3 types of muscarnic
1) M1 receptor (neural ) produces slow excitation of
2) M2 receptor (cardiac) activation slows the heart.
3) M3 receptor (glandular) , causing secretion,
contraction of visceral smooth muscle , vascular
Muscarnic Ach receptors act by way of inosine
triphosphate system & they may also inhibit adenyl
cyclase & thus decreasing cAMP synthesis.
Muscarnic recptors also open or close ion channels
particularly K+ or Ca++ this action occurs through G
Muscarnic receptors relax smooth muscle by an effect
on endothelial cells which produces nitric oxide (NO) .
Nitric oxide ( NO ) relaxes smooth muscles by
stimulating guanylate cyclase & there by increasing
levels of cGMP which in turn activates cGMP
dependent protein kinases.
The number of muscarnic receptors are regulated &
exposure to muscarnic agonist decreases the number
of receptors by internalization of rceptor.
The betz cells of motor cortex uses acetyl choline as
Acetyl choline probably acts as an imporatant
neurotransmitter in basal ganglia which is involved in
control of movements.
Deficits in cholinergic path way in the brain
implicated in some form of Alzheimer's disease.
GABA major fast inhibitory neurotransmitter in the
fore brain. 30% synapses of C.N.S contain GABA.
Glutamic acid dehydrogenase synthesizes
GABA from glutamate in nerve terminal .
3 types of receptors GABA a
GABA a & GABA c are ionotropic receptors & are post
synaptic linked to chloride channel.
GABA b receptors are metabotropic may be pre or
post synaptic & are coupled to ca+ or k+ ion channels
via GTP proteins.
Presynaptic GABA b receptors serve autoreceptors to
inhibit release from nerve terminal.
Binding of GABA leads to an opening of chloride
channels & resultant hyperpolarization.
Glycine is inhibitory neurotransmitter in brain stem &
Post synaptic receptor for glycine is ligand gated
chloride channel that allows influx of Cl- to
hyperpolarize the postsynaptic neuron
Glutamate & aspartate are excitatory
Glutamate is responsible for 75% of excitatory
neurotransmission in brain.
Synthesis of glutamate & aspartate within central
neuron & glial cells is from carbohydrates involved in
Mitochondrial enzyme aspartate transaminase
interconverts glutamate & aspartate.
Glia contains glutamine synthase which converts
glutamate to glutamine.
Glutamine is subsequently transferred to neuron
where it is deaminated to glutamate by glutaminase.
Glial inactivation & specific uptake systems for
glutamate reduces interstitial glutamate levels to
terminate neurotransmitter action & prevent
Monosodium glutamate produces migrainous head
Excessive glutamate can result in neurotoxicity ,
celldeath & neurodegeration seen alzheimer’s disease.
The receptors are subdivided into 5 classes.
1 )NMDA (N – methyl –D –aspartate )
2 )AMPA (α amino 3 hydroxy 5 methyl 4 isoxazole
propionic acid )
3 )The kainate recptor ( isolated from sea weed)
4 )L –AP 4 ( synthetic agonist )
5 )Metabotropic receptors.
First four receptors are cation channels .
Metebotropic receptors are linked to intracellular
production of diacylglycerol,& inositol triphosphate by
phosphoinositide path way.
NMDA is receptor is complex contains 5 distinct sites
1 ) site for transmitter binding glutamate
2 ) a regulatory site that binds glycine.
3 ) a voltage dependent Mg++ binding site
4 ) a site that binds phencyclidine
5 ) a site that binds Zn++.
NMDA receptor opens when glutamate binds & allows
influx of Ca++ & Na++ into the cell.
Mg++ , zn++ , poly amines , & steroids can also
one of the most important controls on the ionic
conductance through the NMDA receptor is voltage
sensitive blocking by Mg++
Activation of AMPA receptor channels may depolarize
the neuron sufficiently to remove the voltage
dependent Mg++ block & activate NMDA channels.
AMPA & NMDA are co activated & are present on the
same part of the neuron.
A separate site that modulates the gating of NMDA
channel binds polyamines such as spermine &
spermidine which are synthesized by neurons.different
concentration dependent effects have observed.
Endogenous Zn reduces NMDA activated current.
Zinc is present in high concentrations in the
hippocampus & released with some neurotransmitter
in nervous system.
Hydrogen ions also modulate the ion conductance
which is maximal at slightly alkaline pH , & reduces
with increasing acidity.
During hypoxic ischemic injury , progressive
acidification resulting from glycolytic metabolism ,
may turn off the NMDA receptor channel.
AMPA receptor is coupled to both Na++ , & K ++
channels. it’s activation opens the above channels,
depolarizes the neuronal cell rapidly, it is responsible
for the majority of rapid excitatory neurotransmission.
Kainate receptor is also coupled to Na++ , k++
Kainate receptor has slower rate of depolarizing
capacity than AMPA receptor.
Excitatory aminoacids are also able to interact with
metabotropic recptors that activate the second
messenger system, these receptors are found both pre
& post synaptically.
Activation result in presynaptic inhibition & post
The spectrum of neurological disorders mediated by
excitotoxicity include epilepsy, stroke ,
neurodegerative disorders ( parkinson’s disease ,
amyotropic lateral sclerosis , AIDS dementia )
Most strokes are caused by thromboembolic events
causing diminished perfusion resulting in reduction of
supply of oxygen & glucose.
3 subsequent stages are there in the development of
brain damage caused by ischemia.
Induction : ischemia causes depolarization of the
neuronal membrane leading to release of glutamate.
Glutamate overexcites the NMDA receptors in adjacent
neuron , leading to abnormally large influxes of Ca++
& Na+ and resultant cell injury or death .
In addition glutamate stimulate AMPA – kainate
receptor ( leading to additional influx of Na+ ) & also
metabotropic receptors , causing the release of ITP &
Amplification : further build up of intra cellular
calcium occurs by following mechanism ,
1) increased intracellular Na+ activates Na+ - Ca++
2)voltage gated Ca++ channels are activated by
3) ITP release Ca++ into cytosol from within
Expression : high levels of intra cellular Ca++ activates
Ca++ dependent nucleases , proteases , &
Degradation of phospholipids
formation of platelet activating factor (PAF) &
release of arachidonic acid
damage by oxygen free radicals
This is called glutamate cascade.
Huntington disease characterized by selective
neuronal death in corpus striatum & glial proliferation
Apoptosis , protein aggregation , & excitotoxins may all
contribute cell death in huntington disease.
Excitotoxicity is by glutamate cascade.
The dopaminergic neurons are found in
nigrostrital , mesolimbic , mesocortical
Dopamine synthesis occurs from tyrosine , tyrosine
hydroxylase is rate limiting enzyme in formation.
Entry of dopamine into synaptic vesicle is is driven by
pH gradient established by a protein in vesicular
membrane that pumps protons into vesicle at the
expense of ATP
Release of dopamine involves exocytosis.
Dopamine has 5 post synaptic recptors
D 1 receptor family(D1 & D5)
D 2 receptor family(D2, D3, D4)
D4 receptor exhibits 5 polymorphic variants.
The effect of dopamine is to increase direct path way
by D 1 recptor, & supress indirect path way by D 2
D 1 receptor activation augments adenylate cyclase (
linked to stimulatory G protein).
D 2 receptor activation decreases the activity of
adenylate cyclase ( linked to inhibitory G protein ).
ATP dependent reuptake of dopamine achieved by a
high affinity transporter in presynatic membrane , this
is incorporated into vesicles & reused again.
Degradation of dopamine occurs within synaptic cleft
or following reuptake ,within presynatic terminal.
Mono amino oxidase B present in the outer membrane
of mitochondria & also in synaptic cleft.
MAO –B & MAO – A are distinguished from each
other by preference for different substrates & by their
different susceptibility to various inhibitors.
Both the above enzymes acts on dopamine to produce
3 – hydroxyphenyl acetaldehyde (DOPAC).
DOPAC converted to homovanillic acid by the action
of catechol o methyl transferase.
parkinson disease is due to loss of dopaminergic
activity & excessive cholinergic activity in basal
Signs of parkinson disease reflects a deficiency of
dopamine in the substantia nigra , corpus striatum (
caudate nucleus & putamen )
Basal ganglia are important for motor control they
subthalamic nucleus .
All circuits in basal ganglia are inhibitory utilizing
GABA except glutamatergic subthalamic input to
globus pallidum internum(GPi) which is excitatory.
Cell damage in parkinson disease reflect a process of
ageing , 13 % of cells of substantia nigra are lost per
decade from 25 age onwards . ( parkinson disease
rarely occurs befor 40 years )
Mutattions in gene encoding α synuclein , a
presynaptic protein involved in neuronal plasticity is
associated with parkinson disease.
Lewy bodies are found strongly stained with
antibodies of α synuclein .
Signs of parkinson disease appear when the level of
dopamine is droped in nigrosriatal system by 80%.
Exposure to high levels of Manganese
( miners) leads to parkinson disease.
Reserpine inhibit dopamine storage & many
neuroleptics block dopamine receptors.
Schizophrenia is a manifestation of
Measurement of dopamine metabolite homovanillic
acid in CSF is high in schizophrenics.
Level of D2 receptors appears to be increased in the
brains of schizophrenics.
Dopamine mimetic drugs ( L dopa) induces
Low dopamine activity in prefrontal cortex of the brain
of schizophrenics correlate well with the negative
Low dopamine activity in prefrontal cortex releases the
inhibitory action on subcortical dopamine neurons
resulting in elevated dopaminergic activity.
Adrenergic neurotransmission is by norepinephrine &
The adrenergic neurons of locus ceruleus , pons , &
medulla project to every area of brain & spinal cord.
Sympathetic postganglionic neurons typically release
NE & E serve important role in the regulation of blood
volume & blood pressure.
Norepinephrine is synthesized from tyrosine .
dopamine β hydroxylase
dopamine β hydroxylase is bound to inner membrane of
synaptic vesicle & release norepinephrine in a
tetrameric glycoprotein form.
The overall system of epinephrine synthesis , storage &
secretion from adrenal medulla are regulated by
neuronal controls & also by glucocorticoid hormones
synthesized in & secreted from adrenal cortex in
Secretion of epinephrine is signaled by neural
response to stress , which is transmitted to adrenal
medulla by way of a preganglionic acetyl cholinergic
A small number of neurons in the medulla contain
phenyl ethenolamine –N- methyl tranferase enzyme
that converts norepinephrine to epinephrine with
SAM as methyl donor.
These neurons project to the thalamus, brainstem ,
Concentration of epinephrine secreting terminals in
the paraventricular nucleus suggests a role in secreton
of oxytocin & vasopressin.
Dense innervation of dorsal motor nucleus of vagus , &
nucleus solitarius suggets role in regulating
cardiovascular & respiratory reflexes.
Receptors on target cells may be either α or β
Receptors are further sub divided into α1, α2, β1 , β2 ,
α1 receptor are located postsynaptically but α2
receptors may be either pre or postsynaptic .
Receptors located presynaptically are autoreceptors
inhibit release of neurotransmitter.
The effects of α1 receptors are mediated by activation
of ITP/ diacyl glycerol second messenger system.
β receptors can be antagonized by action of α1
α2 receptors decease the rate of synthesis of cAMP
through an action on inhibitory G protein.
β1&β2 receptors activates stimulatory G protein to
increase cellular cAMP levels.
Activation of β receptor result in coactivation of β
adrenergic receptor kinase (BARK), this
phosphorylates the receptor.
Phophorylation is prominent mechanism of receptor
Number of β receptors is regulated .
β receptor is phosphorylated & desensitized their
number also decreased if they become internalized.
β receptors can also be increased by denervation.
The number of α receptor is also regulated.
β1 adrenergic receptors principally found in heart &
β2 receptors principally found in lung & cerebellum.
β1 receptors equally prefer NE & E as agonist.
β2 receptors prefer epinephrine to norepinephrine.
In synaptic neurons norepinephrine decreases the
amplitude of calcium spikes.
Excitatory effects of norepinephrine in various parts of
CNS & sympathetic ganglion neuron results from α1
receptor activation. This activity primarily depends on
blockade of a resting K+ conductance as a result
neuron depolarizes & firing rate increases.
Inhibitory effects of norepinephrine results from α2
receptor activation , which results in increase of K+
conductance this hyperpolarizes the neuron &
decreases it’s firing rates.
NE acting at α2 receptor also block Ca++ current.
Both the above inhibitory mechanisms account for the
autoreceptor function of α2 receptors which decreases
α2 adreno receptor activation results in
1) inhibition of transmitter release, (including NE &
Ach from autonomic nerves)
2) platelet aggregation
3) contraction of vascular smooth muscle.
4) inhibition of insulin release.
β1 adreno receptors activation results in
1) increased cardiac rate & force
β2 adreno receptors activation results in 1)
3) relaxation of visceral smooth muscle,
4) hepatic glycogenolysis,
5) muscle tremor.
β3 adreno receptor activation results in lipolysis.
The action of catecholamine neurotransmitters is
terminated by reuptake into presynaptic neuron by
Enzymes involved in metabolism are catechol 0
methyl transferase & monoamino oxidase .
End product of norepinephrine & epinephrine
metabolism is 3 methoxy 4 hydroxy mandelic acid.
More than 95% of body’s serotonin is stored in
platelets & GI tract , only 5% is seen in brain.
Serotonin is distributed in brain regions that affect
behaviour especially the hypothalamus & limbic
Availability of tryptophan is the main factor regulating
synthesis of tryptophan.
Process of synthesis , storage , release , reuptake &
degradation are similar to catecholmines.
Urinary 5 HIAA provides a measure of 5 –HT turn
Functions associated with 5-HT path ways
1)hallucination & behavioural changes,
2)sleep, wakefulness & mood ,
3) feeding behaviour,
4)control of sensory pathway including
Serotonin receptors are metabotropic.
Melatonin a derived product of 5-HT has role in
establishing circadian rhythm.
Histamine has neurotransmitter role in brain.
Acts on metabotropic receptors.
H1 receptors are excitatory & H2 , H3 receptors are
H1 receptors in cortex & RAS contributes to arousal &
Has role in food & water intake, thermoregulation
Nitric oxide synthase is present in many CNS neurons.
NO production is increased by mechanisms that raise
intracellular Ca++ concentration( eg: transmitter
NO affects neuronal functions by increasing cGMP
formation ,producing both inhibitory & excitatory
effects on neurons.
ATP functions as neurotransmitter , it acts via
ionotropic receptors as fast excitatory transmitter , via
metabotropic receptors acts as neuro modulator.
Adenosine exerts inhibitory effects through
Neurons contain CO generating enzyme, heme
oxygenase , have role in cerebellum & olfactory
neurons which have cGMP sensitive ion channels.