Autonomic Nervous System:

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Autonomic Nervous System Introduction to
neurotransmitter and receptor specificity
Thomas Guenthner Professor of Pharmacology College
of Medicine Tel. [phone] Room E418, CMW E-mail
tmg_at_uic.edu
Thanks to Dr. Richard Ye for Powerpoint concepts
and slides
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Knowledge objectives introduced by these two
lectures
Identify the key conceptual similarities and
differences between autonomic cholinergic and
adrenergic pathways including receptor subtypes,
neurotransmitters, transmitter synthesis,
storage, and release, and relative specificities
of drugs that stimulate or inhibit each branch or
activity.
List the major systems or organs innervated by
the autonomic cholinergic and adrenergic systems.

Describe the organ system effects of cholinergic
and adrenergic stimulation or antagonism.
Relate the tissue expression profiles of
cholinergic and adrenergic receptors to their
specific functions.
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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 glads use Ach (nicotinic or
  muscarinic). Dopaminergic innervation in
  sympathetic system renal blood vessels.

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Synapse site most amenable to pharmacologic
manipulation
Na
Precursors (choline/tyrosine)
Synaptic cleft
Precursor
Neurotransmitter
Pre-synaptic nerve cell
Storage
Release
Ca2
Recognition by receptors
Metabolic disposition
Post-synaptic nerve cell
Manipulation possible at 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.
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Key Steps in Neurotransmission
Synthesis Storage
Metabolism
Action potential
Release
Recognition (action)
Reuptake
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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. Exampleneostigm
ine blocks AchE, causing Ach accumulation.
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Otto Loewi (Nobel Laureate, 1936)

• Discovered that stimulation of the vagus of a
  frog heart causes release of a substance that,
  when applied to a second heart, could slow heart
  rate. He called this Vagusstoff, demonstrating
  the chemical basis of neurotransmission.

• Also found that atropine can prevent the
  inhibitory action, but not the release, of
  Vagusstoff.

• Exposure of Vagusstoff to frog heart
  homogenate inactivates it.

• Physostigmine enhances the effect of vagus
  stimulation on the heart, and prevents the
  destruction of Vagusstoff.

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Synthesis of acetylcholine
Choline
Acetylcholine
Choline acetyltransferase


CoA-SH
Acetyl-CoA
CoA
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Synthesis, storage and release of acetylcholine
Na
Choline (10 mM)
Synaptic cleft
Choline
Ach
Nerve impulse
choline acetic acid
NN
Pre-synaptic cell
Ca2
Ach
AchE
Recognition by receptors
Ca2
NM
Post-synaptic cell
CAT choline acetyltransferase AchE
acetylcholinesterase
AchE
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Degradation of acetylcholine
H2O
O
Choline
Acetic acid
AchE

CH3COOH
(CH3)3 NCH2CH2OH
(CH3)3 NCH2CH2O
CCH3
(-)
OH
AchE
Glu202 Tyr337
Ser203 Glu334 His447
600,000 Ach molecules / AchE / min turnover
time of 150 microseconds
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Drug intervention -- Cholinergic transmission
Precursor transport
Hemicholinium
(Rate-limiting)
? Stimulatory ? Inhibitory Solid
Agonistic Dotted Antagonistic
Synthesis
Cholinergic antagonists
Atropine (anti-M) Succinylcholine
(anti-NM) Trimethaphan (anti-NN)
Storage
Vesamicol
Release
Botulinum toxin
Cholinergic agonists (direct acting)
AntiChE
Carbachol Pilocarpine
Reversible (neostigmine) Irreversible (organo-
phosphate)
Receptor action
Degradation by AchE
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An example of indirect agonism
Physostigmines 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.
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Julius Axelrod (Nobel Laureate, 1970)
His discoveries concern the mechanisms which
regulate the formation of norepinephrine in the
nerve cells and the mechanisms which are involved
in the inactivation of this important
neurotransmitter.
Synthesis of Catecholamines
1
3
PNMT
Adrenal medulla
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Regulation of Norepinephrine Synthesis and
Metabolism
a2R
Signal
Uptake-1
DBH
NE
ATP
NE
(-)
bR
Post-synaptic
Ca2
Pre-synaptic
Ca2
Cellular messengers and effects
aR
COMT
Normetanephrine (NMN)
Diffusion, metabolism
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Drug intervention -- Adrenergic transmission
Tyrosine
? Stimulatory ? Inhibitory Solid
Agonistic Dotted Antagonistic
(Rate-limiting)
Metyrosine
TH
Dopa?DA
Reserpine
Adrenergic antagonists
Vesicle (DA?NE)
Phentolamine (a-blocker) Propranolol (b-blocker)
Amphetamine, tyramine, ephedrine
Release
Bretylium, guanethidine
Adrenergic agonists (direct acting)
Cocaine Tricyclic antidepressants
(e.g. imipramine)
Isoproterenol Albuterol
Receptor action
Recapture by Uptake-1
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PNS Receptor Functions
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PNS Receptors - Pharmacological Classification
M1, M3, M5 (Gq coupled)
Muscarinic R
(mAChR)
M2, M4 (Gi coupled)
Cholinergic R
NM (neuromuscular, or muscle type)
Nicotinic R
(nAChR)
NN (neuronal, or ganglion type)
a2
a1,
Adrenergic R
b1,
b2,
b3
D1, D2, D3, D4, D5
Dopamine R
Other receptors (receptors for NANC
transmitters, e.g. nitric oxide, vasoactive
intestinal peptide, neuropeptide Y)
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CNS
Pre-ganglionic
Ganglion
Post-ganglionic
Effectors
Ach
Ach
Cardiac smooth muscles, gland cells, nerve
terminals
Parasympathetic
Cranial
Muscarinic
Nicotinic
Ach
NE
Sympathetic
Cardiac smooth muscles, gland cells, nerve
terminals
Adrenergic (a, b)
Nicotinic
Ach
Ach
Sympathetic
Sweat glands
Muscarinic
Nicotinic
Thoracolumbar
Ach
D
Sympathetic
Renal vascular smooth muscle
Dopaminergic (D1)
Nicotinic
Ach
Sympathetic (adrenal medulla)
Released into blood
Epi
Nicotinic
Ach
Motor (somatic)
Sacral
Skeletal muscle
Nicotinic
Ach acetylcholine
NE norepinephrine
Epi epinephrine
D dopamine
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Adrenergic receptors
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Classification of adrenergic receptors by agonist
potency
a -- NE ? Epi gt Iso b -- Iso gt Epi gt NE
NE norepinephrine Epi epinephrine Iso
isoproterenol
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Signaling properties of adrenergic receptors
Norepinephrine Methyl NE Clonidine
Norepinephrine Epinephrine Phenylephrine
Isoproterenol Albuterol (b2) Dobutamine (b1)
a1
b1,2,3
a2
? cAMP
? Inositol phosphates (IP3)
? cAMP
? Calcium channels
? Diacyl glycerol (DAG)
? K conductance
Mostly excitatory
Mostly excitatory
Mostly inhibitory
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Gs and Gi proteins have different functions
Alpha2 receptor
Beta1 receptor
AC
Gs stimulatory G protein
Gi inhibitory G protein
AC adenylyl cyclase (convert ATP to cAMP)
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Distribution and functions of adrenergic
receptors
a1 postsynaptic effector cells, especially
smooth muscle Vasoconstriction, relaxation of
intestinal smooth muscle, hepatic
glycogenolysis
a2 presynaptic adrenergic nerve terminals
(autoreceptor), platelets, lipocytes,
smooth muscle Inhibition of transmitter release,
platelet aggregation, relaxation of
gastrointestinal smooth muscle
b1 postsynaptic effector cells heart,
lipocytes, brain, presynaptic adrenergic /
cholinergic terminals Increased cardiac rate
force
b2 postsynaptic effector cells smooth muscle,
cardiac muscle Bronchodilation, vasodilation,
relaxation of visceral smooth muscle,
hepatic glycogenolysis
b3 postsynaptic effector cells
lipocytes Lipolysis
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Metoprolol
Nadolol
? b2 antagonistic effect
? half-life
Pindolol
b1 antagonistic Partial b2 agonistic
b1 and b2 antagonistic
Propranolol
Acebutolol
b1 antagonistic Partial b2 agonistic
Atenolol
b1 antagonistic ? half-life
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Dopaminergic receptors
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1
3
PNMT
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Dopaminergic receptors in the periphery
Dopamine receptors play important roles in CNS.
Notably, dopamine neurotransmission is involved
in several diseases including Parkinsons
disease, schizophenia, and attention deficiency
disorder.
There are 5 types of dopamine receptors (D1
D5). In periphery, D1 dopamine receptor mediates
renal vasodilation, and increased myocardial
contractility.
D1,5
D2,3,4
? cAMP
? cAMP
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Cholinergic receptors
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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)

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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. The local depolarization spreads
  to an action potential, or leads to muscle
  contraction when summed with the action of other
  receptors. The ion channel is open during the
  active state.

• Nicotine in small doses stimulates autonomic
  ganglia and adrenal medulla. When large doses are
  applied, the stimulatory effect is quickly
  followed by a blockade of transmission.

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Nicotinic receptor antagonists Competitive vs.
depolarizing
Competitive Physically blocks Ach binding
INHIBITOR
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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 (M4) CNS (inhibitory Gi)
• Neural (M5) CNS (excitatory Gq)
• (Sites of primary expression are listed all are
  found in CNS)

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Muscarinic acetylcholine receptors G
Protein-Coupled Receptors (Metabotropic
Receptors)
M1 (enteric, neuronal)
M2 (cardiac)
M3 (glandular, vascular )
M4 (CNS)
M5 (CNS)
Mostly excitatory CNS excitation Gastric acid
secretion Gastrointestinal motility
? cAMP
? IP3, DAG
? Ca2 channel
Mostly inhibitory Cardiac inhibition Presynaptic
inhibition Neuronal inhibition
? Intracellular Ca2
(Inhibition)
(Stimulation)
Glandular secretion Contraction of visceral
smooth muscle Vasodilation (via NO)

• K conductance

? K conductance
(Slow IPSP)
(Depolarization)
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Intracellular signaling triggered by
acetylcholine in the Heart
Main molecular players M2, heterotrimeric G
Protein Gi, Adenylyl cyclase
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Clinical manifestation of excessive cholinergic
effects
(DUMBELS)
D Defecation U Urination M Miosis B
Bradycardia E Emesis L Lacrimation S
Salivation
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Effects of muscarinic antagonists

• DRY AS A BONE, RED AS A BEET, MAD AS A HATTER.
• Decreased sweating, salivation and lacrimation
• Reflex peripheral (cutaneous) vasodilation to
  dissipate heat (hyperthermia)
• CNS effects of muscarinic inhibition --
  restlessness, delerium, hallucination
• ALSO
• Bronchodilation
• Tachycardia
• Mydriasis (pupil dilation) and Cycloplegia (loss
  of focus)
• GI and Bladder atony

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Physiological Effects of ANS Stimulation and
Inhibition
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Receptor distribution and effects in the
autonomic nervous system
Organ
Receptor
Parasympathetic
Receptor
Sympathetic
Heart
Rate? Force ? Automaticity ? Automaticity
? Force ?
?1 b1 b1 b1 b1
Rate ? Force ? Conduction velocity ? AV block
M2 M2 M2
SA node Atrial muscle AV node Ventricular muscle
Blood vessels
Arterioles
Coronary Skeletal muscle Viscera Skin Brain Erecti
le tissue Salivary gland
Contraction Relaxation Contraction Contraction Con
traction Contraction Contraction Contraction Relax
ation
a1 b2 a1 a1 a1 a1 a1 a1 b2
M3
M3 M3
Relaxation Relaxation
Vein
(Continued, next page)
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Organ
Sympathetic
Receptor
Parasympathetic
Receptor
Viscera
Relaxation Motility ? Contraction Contraction
Relaxation
Bronchiolar SMC Glands GI track Smooth
muscle Sphincters Glands Uterus
b2
M3
Contraction
Secretion Motility ? Relaxation Secretion Gastric
acid secretion Variable
M3 M3 M3 M3 M1
a2, b2 a1 a1 b2
Skin Pilomotor SMC
Contraction (piloerection)
a1
a1, b1
Salivary glands
Secretion
Secretion
M3
Lacrimal glands
Secretion
M3
b1
Kidney
Renin release
Glycogenolysis Gluconeogenesis
b2, a1 ?2, a1
Liver
b3
Lipolysis
Fat
From Rang et al. Pharmacology, 6th Ed. p. 169.
Also, see Katzung, Basic Clinical Pharmacology,
10th Ed. p.86.
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Cardiovascular Pharmacology (Blood Pressure)
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Cardiovascular effects of intravenous infusion of
epinephrine, norepinephrine, and isoproterenol in
man. Norepinephrine (predominantly a-agonist)
causes vasoconstriction and increased
systolic and diastolic BP, with a reflex
bradycardia. Isoproterenol (b-agonist) is a
vasodilator, but strongly increases cardiac force
and rate. Mean arterial pressure falls.
Epinephrine combines both actions.
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Sir Henry Hallett Dale (Nobel laureate, 1936)
(Arterial pressure of an anesthetized cat
was measured)
Two kinds of effects produced by Ach. A. Ach
causes a fall in BP due to vasodilation. B. A
larger dose of Ach also produces bradycardia,
further reducing BP. C. Atropine blocks the
effect of Ach in lowering BP. D. Still under the
influence of atropine, a much larger dose of Ach
causes a rise in BP and tachycardia.
A, B Muscarinic effects of Ach (M3, M2) C
Muscarinic antagonistic effect (M) D. Stimulation
of sympathetic ganglia (NN)
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Receptor distribution and effects in the
autonomic nervous system
Organ
Receptor
Parasympathetic
Receptor
Sympathetic
Heart
Rate? Force ? Automaticity ? Automaticity
? Force ?
?1 b1 b1 b1 b1
Rate ? Force ? Conduction velocity ? AV block
M2 M2 M2
SA node Atrial muscle AV node Ventricular muscle
Blood vessels
Arterioles
Coronary Skeletal muscle Viscera Skin Brain Erecti
le tissue Salivary gland
Contraction Relaxation Contraction Contraction Con
traction Contraction Contraction Contraction Relax
ation
a1 b2 a1 a1 a1 a1 a1 a1 b2
M3
M3 M3
Relaxation Relaxation
Vein
(Continued, next page)
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Intracellular signaling triggered by
acetylcholine in the endothelium
eNOS Nitric oxide synthase
Major molecular players M3, heterotrimeric G
Protein Gq, Ca(2)-CaM, eNOS, NO
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Nitric oxide (NO) signaling pathway for SMC
relaxation
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Pulmonary Pharmacology (Asthma and COPD)
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Ocular Pharmacology (Glaucoma)
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Cholinergic effects
Adrenergic effects

• Contraction of pupillary constrictor muscle
• -- miosis
• Contraction of ciliary muscle - bulge of lens
• -- near vision, ? outflow of aqueous humor

• Contraction of pupillary dilator muscle
• -- mydriasis
• Stimulation of ciliary epithelium
• -- ? production of aqueous humor

Pupillary dilator muscle (a1) Pupillary
constrictor muscle (M3)
Trabecular meshwork
(opened by pilocarpine)
Lens
(M3)
Secretion of aqueous humor (b)