Autonomic Nervous System

Introduction to neurotransmitters and

receptor specificity

DR RABIA ARSHAD
 OBJECTIVES
• The concept of ANS
• The major organs innervated by the autonomic
cholinergic and adrenergic systems
• The main receptors of ANS
• The neurotransmitters of ANS
• The mechanism of action of ANS receptors
• The effects of sympathetic activation on the body
• The effect of parasympathetic activation on the
body
Pharmacological division of cholinergic vs. adrenergic
neurotransmission

• All preganglionic and parasympathetic postganglionic neurons use acetylcholine as

neurotransmitter. Ach is the neurotransmitter at ganglia, NMJ, and muscarinic
tissue synapses.

• Most postganglionic sympathetic neurons use norepinephrine which is an

adrenergic neurotransmitter.

• There are exceptions: Cholinergic transmission in sympathetic system – all

ganglia, adrenal medulla, sweat glands use Ach

• Dopaminergic innervation in sympathetic system utilizes dopamine – renal blood

vessels.
Synapse – site most amenable to pharmacologic manipulation:

Na
+ Precursors
(choline/tyrosine)

Synaptic
Precursor
cleft

Neurotransmitter

Pre-synaptic Storage
nerve cell
Release
Ca2 Recognition
+ by receptors
Metabolic
disposition Post-synaptic
nerve cell

Pre-synaptic neuron: where neurotransmitter is synthesized, stored and released upon

cell activation, or at post-synaptic neuron or effector cell, where neurotransmitter is
detected and its action is translated into cellular activities.
Key Steps in Neurotransmission:

Synthesis & Storage Metabolism

Action
Release Recognition
potential
(action)

Reuptake

Strategies for Pharmacological Intervention:

Block synthesis and storage: Usually rate-limiting steps; produce long-term effects
Block release: Rapid action and effective
Block reuptake increases synaptic neurotransmitter concentrations
Can be selective or non-selective
Interfere with metabolism: Can be reversible or irreversible; blocking metabolism
increases effective neurotransmitter concentrations
Interfere with recognition: Receptor antagonists
Definition of Agonist and Antagonist:
Agonist: (1) A natural ligand that activates a receptor. (2) A drug that has properties
similar to a natural ligand in activating the same receptor.

Antagonist: (1) A receptor-specific blocker. (2) A molecule, such as a drug (e.g.,

enzyme inhibitor) or a physiologic agent (e.g., hormone), that diminishes or prevents the
action of another molecule.

Mode of Action:

Direct-acting: Molecule that physically binds to the target for its effect.
Example: carbachol activates cholinergic receptors.

Indirect-acting: Molecule that exerts effect on the target by interacting with

another non-target site.
Example:neostigmine blocks AchE, causing Ach accumulation.
Synthesis of acetylcholine:

Choline Acetylcholine
CH CH O
3
CH Choline 3
N –CH2–CH2– CH N –CH2–CH2– –C–
3 CH + OH acetyltransferase 3 CH + O CH3
3 + 3 +
O CoA-SH
CoA–S–C–CH3

Acetyl-CoA CoA
Synthesis, storage and release of acetylcholine:

Na Choline
+ (10 mM)

Synaptic
Choline
cleft
ChAT
Ac-CoA Antiporter
Ach Ach

Nerve Ach
choline
impulse Ach + acetic acid
Ach
N
Pre- Ca2 N
synaptic +
Ach
AchE

cell Ca2 Recognition

by receptors
+

N
M
CAT = choline acetyltransferase AchE Post-
AchE = acetylcholinesterase synaptic
cell
Degradation of acetylcholine:

H2
O Choline Acetic acid
O Ach
(CH3)3 N+–CH2– –C– (CH3)3 N+–CH2– + CH3CO
E
CH2–O
(-) CH3 CH2–OH OH
AchE OH
Glu202 Ser203
Tyr337 Glu334 600,000 Ach molecules / AchE
His447
/ min
= turnover time of 150
microseconds
Drug intervention -- Cholinergic transmission

(Rate-limiting) Precursor transport Hemicholinium

: Stimulatory
Synthesis : Inhibitory
Cholinergic antagonists Solid: Agonistic
Dotted: Antagonistic
Atropine (anti-M)
Succinylcholine Storage Vesamicol
(anti-NM)
Trimethaphan
(anti-NN)
Release Botulinum toxin
Cholinergic agonists
(direct acting) AntiChE
Carbachol Ach Reversible (neostigmine)
Pilocarpine
Irreversible (organo-
phosphate)
Receptor Degradation
+ action by AchE
 An example of indirect agonism:

Physostigmine’s effect on acetylcholine receptor is indirect. This

effect is mediated through the inhibition of cholinesterase, which
causes an increase in the local concentration of acetylcholine. The net
effect is agonistic on acetylcholine receptor.
Synthesis of Catecholamines Tyrosine hydroxylase

1
Phenylethanolamine- 3 CH
T
H CH
2 O 2
N-methyl transferase H
H COO
C H
H H
H COO
C H Dopa decarboxylase
O NH O NH
Tyrosin
e
2
DOP
A
2 (L-amino acid
DD (L- decarboxylase)
AAD)
O O
H CH H CH H CH
O H
PNM O H
DBH O 2
H CH T H CH H CH
O 2NHC O 2
NH O 2
NH
Epinephri Norepinephri Dopami
H3 2 2
ne ne ne
Adrenal medulla

Dopamine b-hydroxylase
Regulation of Norepinephrine Synthesis and Metabolism:

Na
+
Tyrosine

Tyrosine
TH
DD a2R
Dopa Dopamine
Signal (DA)
DBH NE Uptake-1
ATP
NE
(-)
bR
Ca2 DBH Post-
Pre- NE
+ ATP
NE synaptic
synaptic Ca2
NE
Cellular messengers
+ and effects
aR

COMT

Diffusion, Normetanephrine (NMN)

metabolism
Drug intervention -- Adrenergic transmission

: Stimulatory Tyrosine
: Inhibitory
(Rate-limiting) T Metyrosine
Solid: Agonistic
Dotted: Antagonistic H
Dopa DA
Reserpine
Adrenergic antagonists
Vesicle (DA NE)
Phentolamine (a-blocker)
Propranolol (b-blocker) Amphetamine, tyramine,
ephedrine
Release
Adrenergic agonists Bretylium, guanethidine
(direct acting)
Cocaine
Isoproterenol Tricyclic antidepressants
NE
Albuterol (e.g. imipramine)

Receptor Recapture
+ action by Uptake-1
PNS Receptor Functions
PNS Receptors - Pharmacological Classification:
M1, M3, M5 (Gq coupled)
Muscarinic R
(mAChR)
M2, M4 (Gi coupled)
Cholinergic R
Nicotinic R NM (neuromuscular, or muscle type)
(nAChR)
NN (neuronal, or ganglion type)
a1, a2
Adrenergic R
b1, b2, b
3

Dopamine R D1, D2, D3, D4, D5

Other receptors (receptors for NANC transmitters,

e.g. nitric oxide, vasoactive intestinal peptide, neuropeptide Y)
Classification of adrenergic receptors by agonist potency

a -- NE Epi > Iso NE = norepinephrine

Epi = epinephrine
b -- Iso > Epi > NE Iso = isoproterenol

O O O
H CH H CH H CH
O H O H O H
H CH H CH CH
H
O 2
NHC O 2
NH 2
O N
E H3 N 2
Is H
CH(CH
E
pi o 3)2
Signaling properties of adrenergic receptors

Norepinephr Norepinephr Isoproterenol

ine ine Albuterol
Epinephrine Methyl NE (b2)
Phenylephri Agonist Clonidine Agonist Dobutamine Agonist
ne aa1 a2 (b1)bb1,2,3

Gq Gi Gs

Inositol phosphates
(IP3) cAMP cAMP
Calcium channels
Diacyl glycerol (DAG)
K+ conductance

Mostly excitatory Mostly inhibitory Mostly excitatory

Receptor distribution and effects in the autonomic nervous system:

Orga Sympathet Recept Parasympathe Recept

n
Hea ic or tic or
SA node
rt Rate 1 Rate M
b1 2
Atrial muscle Force Force
AV node b1 M
Automaticit Conduction 2
y velocity M
Ventricular b1 2
AV block
muscle
Blood b1
Automaticit
vessels
Arteriol y
Coronary
es Contracti a
Force M
Skeletal on 1
b 3
muscle Relaxatio 2
Viscera n a
Skin Contracti 1
Relaxati M
a 3
Brain on on
Vei
Erectile Contracti
1
M
a Relaxati 3
ntissue on 1 on
Salivary Contracti a
(Continued,
gland next on
1

page) a
Contracti 1
 Orga Sympathet Recept Parasympathe Recept
nViscer ic or tic or
aBronchiolar Relaxatio b Contracti M
SMC n
2 Secretion
on M
3
3
Glands a2,
GI track Motility M
b2
Smooth Motility a1 Relaxation 3

muscle Secretion M
3
Sphincters Contracti Gastric acid
M
Glands on a1 secretion 3
Skin b2 M
Uterus
Pilomotor Contraction a Variable 1

SMC (piloerection)
Contracti 1
Salivary Secretio a1, Secretio M
on b1 3
glands
Lacrimal n n
Secretio M
Relaxatio 3
glands
Kidne Renin b n
n
y release
1
Liv Glycogenolysi b2,
er s a1
Fa Lipoly
Gluconeogene b 2,
3
t sis a1
From: Rang et al. Pharmacology, 6th Ed. p. 169. Also, see Katzung, Basic & Clinical
Pharmacology, 10th Ed. p.86.
 Dopaminergic receptors
Dopamine receptors play important roles in CNS. Notably, dopamine
neurotransmission is involved in several diseases including Parkinson’s disease,
schizophenia, and attention deficiency disorder.

There are 5 types of dopamine receptors (D1 – D5). In periphery, D1 dopamine

receptor mediates renal vasodilation.

Agonist Agonist
D1,5 D2,3,4

Gs Gi

cAMP cAMP
Cholinergic receptors: Nicotinic

Nicotiana
tabacum
(cultivated
tobacco)

“Nicotinic actions” -- similar to those induced by nicotine; action mediated by

nicotinic cholinergic receptors:

• stimulation of all autonomic ganglia (NN)

• stimulation of voluntary muscle (NM)
• secretion of epinephrine from the adrenal medulla (NN)
Nicotinic acetylcholine receptor: Function

Ligand-gated ion (Na+) channel

- an “Ionotropic Receptor”

•Acetylcholine binds to the a-subunits of the receptor making the membrane more
permeable to cations (sodium) and causing a local depolarization.

•Nicotine in small doses stimulates autonomic ganglia and adrenal medulla but if large doses are
applied, the stimulatory effect is quickly followed by a blockade of transmission.
Cholinergic receptors: Muscarinic

“Muscarinic actions” -- reproduced by injection of

muscarine, from Amanita muscaria (fly agaric).
Similar to those of parasympathetic stimulation

Multiple muscarinic cholinergic receptors distributed

in different tissues. Therefore, the “muscarinic
actions” are dependent on the receptors in different
tissues and cells.

• Neural/enteric (M1): CNS, ENS, gastric parietal cells (excitatory; Gq)

• Cardiac (M2): atria & conducting tissue; presynaptic (inhibitory; Gi)
• Glandular/endothelial (M3): exocrine glands, vessels (excitatory; Gq)
• Neural and periphery (M4): CNS (inhibitory; Gi)
• Neural (M5): CNS (excitatory; Gq)
 Muscarinic acetylcholine receptors –
G Protein-Coupled Receptors

M1 M2
(enteric, neuronal) (cardiac)
M3 M4
(glandular, vascular ) (CNS)
Agonist Agonist
M5
(CNS)

Gq Mostly excitatory Gi
IP3, CNS excitation
Gastric acid secretion cAMP
DAG
Intracellular Ca2+ Mostly inhibitory Ca2+ channel
Gastrointestinal motility Cardiac inhibition (Inhibition)
(Stimulation) Glandular secretion Presynaptic inhibition
Contraction of visceral Neuronal inhibition K+ conductance
K+ conductance smooth muscle (Slow IPSP)
(Depolarization) Vasodilation (via NO)
Intracellular signaling triggered by acetylcholine in the Heart

Main molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase

Receptor distribution and effects in the autonomic nervous system:

Orga Sympathet Recept Parasympathe Recept

n
Hea ic or tic or
SA node
rt Rate 1 Rate M
b1 2
Atrial muscle Force Force
AV node b1 M
Automaticit Conduction 2
y velocity M
Ventricular b1 2
AV block
muscle
Blood b1
Automaticit
vessels
Arteriol y
Coronary
es Contracti a
Force M
Skeletal on 1
b 3
muscle Relaxatio 2
Viscera n a
Skin Contracti 1
Relaxati M
a 3
Brain on on
Vei
Erectile Contracti
1
M
a Relaxati 3
ntissue on 1 on
Salivary Contracti a
(Continued,
gland next on
1

page) a
Contracti 1
 Orga Sympathet Recept Parasympathe Recept
nViscer ic or tic or
aBronchiolar Relaxatio b Contracti M
SMC n
2 Secretion
on M
3
3
Glands a2,
GI track Motility M
b2
Smooth Motility a1 Relaxation 3

muscle Secretion M
3
Sphincters Contracti Gastric acid
M
Glands on a1 secretion 3
Skin b2 M
Uterus
Pilomotor Contraction a Variable 1

SMC (piloerection)
Contracti 1
Salivary Secretio a1, Secretio M
on b1 3
glands
Lacrimal n n
Secretio M
Relaxatio 3
glands
Kidne Renin b n
n
y release
1
Liv Glycogenolysi b2,
er s a1
Fa Lipoly
Gluconeogene b 2,
3
t sis a1
From: Rang et al. Pharmacology, 6th Ed. p. 169. Also, see Katzung, Basic & Clinical
Pharmacology, 10th Ed. p.86.
Nitric oxide (NO) signaling pathway for SMC relaxation

M3
r Second
Gq messenger
Cardiovascular Pharmacology
(Blood Pressure)
Ocular Pharmacology
(Glaucoma)
 Cholinergic effects: Adrenergic effects:

• Contraction of pupillary constrictor muscle • Contraction of pupillary dilator muscle

-- miosis -- mydriasis
• Contraction of ciliary muscle - bulge of lens • Stimulation of ciliary epithelium
-- near vision, outflow of aqueous humor -- production of aqueous humor

Pupillary dilator
muscle (aa11)
Pupillary constrictor muscle (M3)

Trabecular
(opened by
meshwork
pilocarpine)
Len
s

(M3
) Secretion of aqueous humor (bb)