Neurotransmitters of the autonomic nervous system are synthesized in presynaptic neurons and stored in vesicles. When an action potential reaches the presynaptic terminal, calcium influx causes vesicles to fuse with the membrane and release neurotransmitters into the synaptic cleft. Neurotransmitters then bind and activate receptors on the postsynaptic cell, eliciting a response. Acetylcholine is the main neurotransmitter of the parasympathetic nervous system and binds nicotinic and muscarinic receptors. Norepinephrine and epinephrine are the main neurotransmitters of the sympathetic nervous system and bind adrenergic receptors. Neurotransmitters are removed from the synaptic cleft primarily by reuptake or enzymatic breakdown to terminate their

1. Topic : Neurotransmitters
of ANS, their synthesis,
release & fate
Zulcaif Ahmad
1

2. Chemical Messengers
• Four types of chemical messengers
– Paracrines
• Local chemical messengers
• Exert effect only on neighboring cells in
immediate environment of secretion site
– Neurotransmitters
• Short-range chemical messengers
• Diffuse across narrow space to act locally on
adjoining target cell (another neuron, a muscle,
or a gland)

3. Chemical Messengers
– Hormones
• Long-range messengers
• Secreted into blood by endocrine glands in
response to appropriate signal
• Exert effect on target cells some distance away
from release site
– Neurohormones
• Hormones released into blood by
neurosecretory neurons
• Distributed through blood to distant target cells

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4

5. Definition
A chemical released by one
neuron that affects another
neuron or an effector organ
(e.g., muscle, gland, blood
vessel)

6. R.E.B, 4MedStudents.com, 2003
Neurotransmitters
• Properties of neurotransmitters:
1) synthesized in the presynaptic neuron
2) Localized to vesicles in the presynaptic neuron
3) Released from the presynaptic neuron under
physiological conditions
4) Rabidly removed from the synaptic cleft by uptake or
degradation
5) Presence of receptor on the post-synaptic neuron.
6) Binding to the receptor elicits a biological response
6

7. 7

8. Neurotransmitters found in the nervous system
EXCITATORY
Acetylcholine
Aspartate
Dopamine
Histamine
Norepinephrine
Epinephrine
Glutamate
Serotonin
INHIBITORY
GABA
8
Glycine

9. Neurotransmitter of
para sympathetic nervous system
• Acetylcholine
9

10. Acetylcholine synthesis:
• In the cholinergic neurons acetylcholine is
synthesized from choline. This reaction is
activated by cholineacetyltransferase
As soon as acetylcholine is synthesized,
it is stored within synaptic vesicles.
10

11.  1)When the nerve impulse (Action potential) moves down the presynaptic
axon to the terminal bulb the change in the membrane action potential
causes the opening of voltage gated calcium channels open allowing Ca 2+
ions to pass from the synaptic cleft into the axon bulb.
 2) Within the bulb the increase
 in Ca2+ concentration causes the
 synaptic vesicles that contain
 acetylcholine to fuse with the
 axonal membrane and open
 spilling their contents into
 the synaptic cleft.
11

12. Neurotransmitter Receptors in the
ANS

14. CHOLINERGIC RECEPTORS
• Acetycholine (Ach) action differs
depending on the type of receptor it
interacts with
• Ach action is mimicked by nicotine in
some organs and mimicked by
muscarine in others 
nicotinic cholinergic receptors
muscarinic cholinergic receptors

15. Cholinergic Receptors
• Nicotinic:
Ligand-gated ion channels (+)
allows entry of sodium and calcium ions
• Muscarinic:
G protein-coupled receptors (+)
activate G proteins to induce
downstream effects

16. Insert Brody Fig 8-10 p.98

17. Nicotinic Cholinergic Receptors
• Primary action of Ach at P and S
ganglia are mediated by activation of
ganglionic NICOTINIC receptors
(similar to that in the CNS and immune
cells but different from that in the
skeletal muscle at the NMJ)
• These different types of nicotinic
receptors allow for selective action (+ or
-) of different agonist and antagonist

18. Muscarinic Cholinergic Receptors
• Mediates responses to Ach at the
parasympathetic neuroeffector junction
• Subtypes M1 to M5:
M1autonomic ganglia- modulates
effects of nicotinic receptor activation
M2 heart
M3 glands, smooth muscles
M4, M5?

21. Binding of acetylcholine to the
postsynaptic receptors:
 The postsynaptic membrane of the receptor dendrite has specific cholinergic receptors
toward which the neurotransmitter diffuses. Binding of acetylcholine trigger the
opening of ion channels in the postsynaptic membrane initiating action potential that
can pass in the next axon.
Acetylcholine receptors:
 Acetylcholine receptors are ion channels receptors made of
many subunits arranged in the form [(α2)(β)(γ)(δ)].
 When Acetylcholine is not bounded to the receptors, the
bulky hydrophobic leu side close the central channels
preventing the diffusion of any ions.
 Binding of two acetylcholine molecules to the receptors will
rotate the subunits in which the smaller polar residues will line
the ion channel causing the influx of Na+ into the cell and
efflux of K+ resulting in a depolarization of the postsynaptic
neuron and the initiation of new action potential.
21

22. Removal of Acetylcholine from the synaptic cleft:
 In order to ready the synapse for another impulses:
 1) The neurotransmitters, which are released from the synaptic vesicles, are
hydrolyzed by enzyme present in the synaptic cleft “Acetylcholinestrase” giving
choline, which poorly binds to acetylcholine receptors.
Acetylcholinestrase
Acetylcholine + H2O Choline + H+ acetate
 2) The empty synaptic vesicles, which are returned to the axonal terminal bulb
by endocytosis, must be filled with acetylecholine.
22

23. Structure of AchE
• Acetylcholinesterase (AchE) is an enzyme,
which hydrolyses the neurotransmitter
acetylcholine. The active site of AChE is
made up of two subsites, both of which are
critical to the breakdown of ACh. The
anionic site serves to bind a molecule of
ACh to the enzyme. Once the ACh is
bound, the hydrolytic reaction occurs at a
second region of the active site called the
esteratic subsite. Here, the ester bond of
ACh is broken, releasing acetate and
choline. Choline is then immediately taken
up again by the high affinity choline uptake
system on the presynaptic membrane.
23

24. Neurotransmitters of sympathetic
nervous system
• Norepinephrine
• Epinephrine
24

25. Catecholamine Synthesis (Dopamine,
Norepinephrine and Epinephrine).
 1) First Step: Hydroxylation:
 In this step: the reaction involves the conversion of tyrosine, oxygen
and tetrahydrobiopterin to dopa & dihydrobiopterin. This reaction
is catalyzed by the enzyme tyrosine hydroxylase. It is irreversible
reaction.
 2) Second step: Decarboxylation:
 In this step: the dopa decaboxylase will catalyze the decaoxylation of
dopa to produce dopamine. The deficiency of this enzyme can cause
Parkinson’s disease. It is irreversible reaction. The cofactor in this
reaction is the PLP (pyridoxal phosphate). In the nerve cells that
secrete dopamine as neurotransmitter the pathway ends at this step.
25

26. Catecholamine Synthesis (Dopamine,
Norepinephrine and Epinephrine).
3) Third step: Hydroxylation:
This reaction is catalyzed by the enzyme dopamine β- hydroxylase.
The reactants include dopamine, O2 and ascorbate (vitamin C).
The products are norepinephrine, water and dehydroascorbate. It
is an irreversible reaction). The end product in noradrenergic
cells is norepinephrine and the pathway ends her.
4) Forth step: Methylation:
This reaction is catalyzed by phenylethanolamine N-
methyltransferase. Norepinephrine and S-adenosylmethionin
(ado-Met) form epinephrine and S-adenosyl homocysteine (ado-
Hcy).
26

27. 27

28. 28

29. Epinephr COMT +
ine MAO Vanillylmandelic
Norepineph
acid
rine
COMT +
Dopamin MAO Homovanillic
e acid
Neuronal re-uptake and degradation of
catecholamines quickly terminates hormonal or
neurotransmitter activity.
Cocaine binds to dopamine receptor to block re-
uptake of dopamine
Figure 3. Degradation of epinephrine, norepinephrine and dopamine
Dopamine continues to stimulate receptors of the
via monoamine oxidase (MAO) and catechol‑O‑methyl-transferase
postsynaptic nerve.
(COMT)

30. Adrenergic Receptors
• NE and Epi can activate more than one
type of adrenergic receptor
• β receptors (1,2, and 3 subtypes)
∀ α1 (3 subtypes) and α2 (3 subtypes)

31. Prejunctional autoreceptors
• Prejunctional α2 receptors are present
in adrenergic and cholinergic nerve
terminals
• Activation of these result to decrease in
further release of NTS presynaptic
inhibitory autoreceptor mechanism
(regulatory function)

32. Figure 2. Regulation of the Stress
release of catecholamines Chronic
Hypothalamus
and synthesis of epinephrine regulation
in the adrenal medulla ACTH
chromaffin cell. from adrenal
Cortisol cortex via intra-
Tyrosine adrenal portal
system
Acute L- DP
regulation Dopa N
induction
granu DPN
Neuron
....
....
...
... . Ca2+
le ↓
NE
... N
PNMT
Epinephrine
⊕ E E E E
acetylcholine neuro-
promot NE E
es secret
Adrenal
exocyt E E ory
Medulla
osis EEE ENE granul
Chromaffin
EE es
Cell NE

33. Table 1. Classification of Adrenergic Hormone Receptors
Second
Receptor Agonists G protein
Messenger
alpha1 (α1) E>NE IP3/Ca2+; DAG Gq
alpha2 (α2) NE>E ↓ cyclic AMP Gi
beta1 (β1) E=NE ↑ cyclic AMP Gs
beta2 (β2) E>>NE ↑ cyclic AMP Gs
E = epinephrine; NE = norepinephrine
Synthetic agonists:
isoproterenol binds to beta receptors
phenylephrine binds to alpha receptors
(nose spray action)
Synthetic antagonists:
propranolol binds to beta
receptors
phentolamine binds to alpha

34. β1 or β2 α2 receptor
receptor
Gs Gi
αs β αi β
γ β β
γ γ γ
GTP GTP
αi
αs
GTP GTP
⊕ 
inactive
ACTIVE
X inactive
adenylyl adenylyl
cyclase adenylyl
cyclase cyclase
ATP cyclic AMP
Figure 5. Mechanisms of β1, β2, and α2 agonist effects on adenylyl
cyclase activity

35. Role of cyclic AMP second messenger pathway

37. Other Neurotransmitters:
Neurotransmitter Derived from Enzyme
Histamine Histidine Histidine
decarboxylase
GABA Glutamate Glutamate
(γ-Amino decarboxylase
butyrate)
Nitric Oxide Arginine Nitric Oxide
Synthase
37

38. Summary:
Neurotransmitter Derived Site of Synthesis
Molecule From
Acetylcholine Choline CNS, parasympathetic nerves
Serotonin Tryptophan CNS, chromaffin cells of the gut, enteric
5-Hydroxytryptamine (5-HT) cells
GABA Glutamate CNS
Histamine Histidine hypothalamus
Epinephrine Tyrosine adrenal medulla, some CNS cells
synthesis pathway
Norpinephrine Tyrosine CNS, sympathetic nerves
synthesis pathway
Dopamine Tyrosine CNS
synthesis pathway
Nitric oxide, NO Arginine CNS, gastrointestinal tract

39. Original Dale’s Law (1950’s)
“A mature neuron makes use of the same transmitter
substance at all of its synapses”
Discovery of peptide transmitters
Modified Dale’s Law = “A mature neuron makes
use of the same combination of chemical
transmitters at all of its synapses.”

40. Modified Dale’s Law – when co- secretion occurs, it
usually involves a small molecule transmitter and one
or more peptides
Small Molecule Transmitter Peptide
AcH VIP
Norepinephrine Somatostatin + enkephalin +
neurotensin
Dopamine Cholecystokinin + enkephalin
Epinephrine Enkephalin
Substance P + TRH
Serotonin