Neurotransmitters

1. Neurotransmitters

2. Discovery of Neurotransmitters
•Otto Loewi, an Austrian scientist, discovered
the first neurotransmitter in 1921.
•He used two frog hearts.
•One heart was still connected to the vagus
nerve.
•Heart #1 was placed in a chamber that was
filled with saline.
•This chamber was connected to a second
chamber that contained heart #2.
•Fluid from chamber #1 was allowed to flow
into chamber #2.

3. Loewi’s Results
•Electrical stimulation of the vagus nerve
attached to heart #1 caused heart #1 to slow
down.
•After a delay, heart #2 also slowed down.
•Loewi hypothesized that electrical stimulation
of the vagus nerve released a chemical into
the fluid of chamber #1 that flowed into
chamber #2.
•He called this chemical "Vagusstoff".
•We now know this chemical as the
neurotransmitter acetylcholine.

4. Otto Loewi’s Experiment

5. What is a Neurotransmitter?
•A substance that is released at a
synapse by a neuron and that effects
another cell, either a neuron or an
effector organ, in a specialized manner
•This seems clear, but application
becomes fuzzy

6. Neurotransmitter Criteria
•Chemical messengers must meet 4 criteria to be
considered transmitters:
–It is synthesized by a neuron.
–It is present in the presynaptic terminal and is
released in amounts sufficient to exert a
defined action on a postsynaptic neuron or
effector organ.
–When given as a drug, it mimics the action of
naturally occurring transmitter in the body
exactly.
–A specific mechanism exists for removing it.

7. Chemical Synaptic
Transmission
•4 steps:
–Synthesis of transmitter
–Storage & release of transmitter
–Interaction of transmitter with
receptor in postsynaptic membrane
–Removal of transmitter from synaptic
cleft

8. Classifying Neurotransmitters
•Once divided into 2 classes:
–Cholinergic – use acetylcholine (ACh)
–Adrenergic - use norepinephrine or
epinephrine
•Now know there are many more types
•2 large classes:
–Small molecules
–Neuroactive peptides (short chains of
amino acids)

9. Manufacture of Large Molecule
Transmitters
•Peptides
–Examples: substance P, somatostatin, leu-enkephalin,
met-enkephalin, vasoactive intestinal polypeptide (VIP),
bombesin
•Occurs in soma
•Peptide synthesized in rough endoplasmic reticulum
•Packaged in Golgi apparatus
•Transported down axon to presynaptic ending of the axon
terminal
–secretory vesicles transported down axon by
orthograde axonal transport

10. Manufacture of Small Molecule
Transmitters
•Small molecule transmitters (amino acids and amines)
–Examples of amino acid neurotransmitters: gamma-amino
butyric acid (GABA), glutamate (Glu), glycine (Gly)
–Examples of amine neurotransmitters: acetylcholine (ACh),
dopamine (DA), epinephrine, histamine, norepinephrine (NE),
serotonin (5-HT)
•Occurs in axon terminal
•Precursor molecule is transformed by synthetic enzyme into
neurotransmitter molecule
•Neurotransmitter molecules are gathered by transporter
molecules and packaged in synaptic vesicles

11. Small Molecule Neurotransmitters
•Nine such substances are accepted as
neurotransmitters:
–8 are amines
–The non amine is ATP
•Synthesis of these neurotransmitters is
catalyzed by enzymes
•Acetylcholine - perhaps the most
important small molecule transmitter

12. Acetylcholine
•Acetylcholine is the transmitter used by
motor neurons of the spinal cord
•Released at all vertebrate neuro-
muscular junctions
•Present in autonomic & parasympathetic
neurons
•Used in many brain synapses

13. Acetylcholine Synthesis
•Synthesis uses the enzyme choline
acetyltransferase (ChAT)
•Takes acetyl group from acetyl CoA in
cytosol
•Takes choline from extracellular fluid
(rate limiting step)

14. Cholinergic Neurons
•Use acetylcholine as a neurotransmitter
•2 types of receptors
–Nicotinic receptor - transmitter-gated ion
channel
–Muscarinic receptor - G-protein-coupled
receptor using short-cut pathway to close
potassium channel
•Removal
–degraded by acetylcholine esterase (AChE)
–AChE is the target of many nerve gases and
insecticides

15. Biogenic Amine Transmitters
•The rest of the 8 amines
•Includes serotonin & the
catecholamines (dopamine, epinephrine
& norepinephrine)
•All catecholamines are synthesized from
the amino acid, tyrosine.
–share a common biosynthetic pathway
–pathway uses 5 enzymes

16. Dopaminergic Neurons
•Use dopamine, norepinephrine, or
epinephrine as neurotransmitters
•Synthesis pathway:
–Tyrosine hydroxylase (TH) makes tyrosine
into dopa
–Dopa decarboxylase makes dopa into
dopamine (DA)
•If the neuron is dopaminergic, the
pathway stops here

17. Noradrenergic & Adrenergic Neurons
•The synthesis pathway continues from
dopamine:
–Dopamine beta-hydroxylase (DBH) makes
dopamine into norepinephrine
•If the neuron is noradrenergic, the pathway
stops here,
•Or the pathway can continue:
–Phentolamine N-methyltransferase (PNMT)
makes norepinephrine into epinephrine
•If the neuron is adrenergic, the pathway goes
the whole way to this point

18. Summary of Catecholamine Synthesis
•All catecholamines have a catechol nucleus & a 3,4-
dihydroylated benzene ring
•The 1st enzyme, tyrosine hydroxylase, converts
tyrosine to L-dihydroxyphenylalanine (L-DOPA)
•L-DOPA is a precursor for all catecholamines
•The 2nd step converts L-DOPA to dopamine & CO
2
•The 3rd step converts dopamine to norepinephrine
•The 4
th
step converts norepinephrine to epinephrine

19. Catecholamine Synthesis

20. Norepinephrine
•In the CNS, norepinephrine is used by
neurons of the locus coeruleus, a
nucleus of the brainstem with complex
modulatory functions
•In the peripheral nervous system,
norepinephrine is the transmitter of the
sympathetic nervous system
•Norepinephrine can then be converted
to epinephrine

21. Removal of Catecholamines
•All three catecholamines are removed
by selective reuptake by the presynaptic
axon terminals
•They are either reused or degraded by
monoamine oxidase (MAO)
•Amphetamines and cocaine block the
reuptake of catecholamines, thereby
prolonging their synaptic action

22. Norepinephrine

23. Dopamine & Norepinephrine

24. Close Cousins?

25. Serotonin
•Derived from the amino acid, tryptophan
•Belongs to a group of compounds called
indoles
•Serotonergic neurons are found in the
brainstem
•Involved in regulating attention & other
complex functions

26. Serotonin Synthesis
•2 enzymes synthesize serotonin
•Synthesis:
•Tryptophan (from the diet via the blood
stream) is converted to 5-HTP by
tryptophan hydroxylase
•5-HTP is converted to serotonin (5-HT)
by 5-HTP decarboxylase

27. Serotonergic Neurons
•Use serotonin (5-HT) as a neurotransmitter
•Because tryptophan comes from the diet,
serotonergic neurons can be quickly affected
by dietary deficiencies in tryptophan
•Removal:
–Selective reuptake by the presynaptic axon
terminals
–Either reused or degraded by MAO

28. Seratonin

29. Importance of Amine Transmitters
•These compounds (serotonin, dopamine, epinephrine
& norepinephrine) play an important role in mental &
neurological dysfunction:
•Depression
–antidepressant drugs enhance neurotransmission
at serotonergic and adrenergic synapses
•Schizophrenia
–involves dopaminergic neurotransmission
•Drug addiction
•Parkinson's disease
–associated with decreased production of dopamine
–treated with L-DOPA

30. Neuropharmacology
•Many neurological diseases and mental
disorders represent malfunctions of the
synaptic transmission
•These can often be treated by drugs which
restore synaptic transmission.
•Inhibitors or receptor antagonists:
–bind to postsynaptic receptor and block normal
action of a neurotransmitter
•Receptor agonists:
–mimic the actions of normal neurotransmitters

31. What Drugs?

32. Histamine
•Acts as a local
hormone (autocoid)
•Involved in control
of blood vessels,
inflammatory
response, etc.
•Also acts as a
neurotransmitter in
invertebrates

33. Amino Acid Transmitters
•Unlike acetylcholine & biogenic amines, these are
universal parts of cells
•Glycine & glutamate are common parts of
proteins
•GABA
–is synthesized from glutamate
–is a major inhibitory transmitter at many sites in brain
•Common amino acids act as transmitters in some
neurons, not in others
–shows that the presence of a substance doesn’t make
it a transmitter

34. ATP & Adenosine
•ATP & degradation products such
adenosine can serve as
neurotransmitters at some synapses

35. Neuroactive Peptides
•More than 50 pharmacologically active peptides
are known
•Serve important functions:
–Some modulate emotions
–Some located in regions of brain involved in
pain and pleasure perception
–Substance P
–Endorphins/Enkephalins
•Others respond to stress
–Endorphins

36. Families of Neuroactive Peptides
•Grouped into families:
–Opioid
–Neurohypophyseal
–Tachykinins
–Secretins
–Insulins
–Somatostatins
–Gastrins

37. Transmitter Binding
•The same transmitter can bind different
receptors, resulting in different actions.
•Receptor binding determines the effect, not
the transmitter itself.
•In related animals, each type of transmitter
binds to a family of receptors and is
associated with certain functions
•Example: acetylcholine = synaptic excitation
at neuromuscular junctions in vertebrates

38. Transmitter Binding

39. Dale's Principle
•Dale postulated that each neuron releases
one and only one neurotransmitter
•This is generally true for amino acid and
amine neurotransmitters
–however, a peptide often accompanies the
amino acid or amine
•Sometimes many peptides are released
from one neuron

40. Which Neurotransmitter?
•How is the neurotransmitter traffic
controlled?
–Slow or intermittent activity causes the
release of the amino acid or amine
transmitter
–Only sustained high levels of activity, or
many long bursts cause the peptides to be
released