1.
Neurotransmission
Brian J. Piper, Ph.D., M.S.

2.
Goals
• Introduction to neurocommunication
• Families of receptors (2)
• Inactivation of neurotransmission (3)

3.
Otto Loewi
• Discovered “Vagusstoff” later
known as acetylcholine
• “father of neuroscience”
• Nobel Prize 1936

4.
Types of Synapses
• Electron Microscope: Beams of electrons are
presented to a thin section, 50 pm (10-12)
resolution

5.
Neurotransmitter Criteria
• 1) Found and made presynaptically.
• 2) Mechanism for inactivation.
• 3) Stimulating neuron releases it.
• 4) Receptors found postsynaptically.
• 5) Applying substance has biological effect.
• 6) Antagonizing inhibits biological effect.
“neuromodulators”: don’t meet all criteria 1 to 6

6.
Classical Neurotransmitters
• Amino Acids: GABA, Glutamate
• Monoamines:
dopamine, norepinephrine, serotonin
• Acetylcholine (ACh)

7.
“Dale’s Principle”
• Old View: Each neuron releases one, and only
one, neurotransmitter (-ergic)
• New View: neurons typically contain two+
neurotransmitters (classical & non-classical)
Henry Dale, M.D.
1875-1963

8.
Non-Classical Transmitters
• Peptides: short (<50) strings of amino
acids, Valine-Glycine-Serine-Alanine… e.g. NPY
C terminal: COOH
N terminal: NH2
Arginine, Proline, Lysine, Phenylalanine,
Methionine, Histidine, Aspartic Acid, Valine

9.
Non-classical Neurotransmitters
• Peptides: Corticotropin-releasing factor
(CRF), endorphins
• Lipids: Anandamide
• Gases: Nitric Oxide

10.
Neurotransmitter Comparison
Classical Non-Classical
Discovery 1950’s 1980’s
Concentration High Low
# Few Many
Synthesis Anywhere Soma

11.
Co-Transmitters
Amine/Amino Acid Peptide
Dopamine Cholecystokinin (CCK)
Norepinephrine enkephalin
Epinephrine neurotensin
Serotonin substance P
Acetylcholine somatostatin
Gamma aminobutyric acid (GABA) motilin
Stahl, S. (2000). Essential Psychopharmacology, p. 20.

12.
Axon Terminal

13.
Brakes I: Inactivation of
Neurotransmitter:
• Enzyme: A + B __ENZ____> AB
• Enzyme: CD __ENZ____> C + D

14.
Brakes II
• Autoreceptors: this receptor (“auto” = “self”)
can act to inhibit further neurotransmission
– Terminal (axon) autoreceptors: inhibit
neurotransmitter release
– Somatodendritic autoreceptors: reduce rate of
action potentials

15.
Brakes III: Transporters
• Proteins that move molecule from one place
to another, examples:
– SERT: serotonin transporter
– NET: norepinephrine transporter
– DAT: dopamine transporter
Inside
----------------------------------------------------------------------
Outside

16.
Brakes III: Transporters
• Structure: 12 transmembrane regions
• What happens if you inhibit brakes?

17.
Post-synaptic (Terminology Refresher)
• Ligand: substance that binds to a receptor
• Ion: atom where # electrons ≠ # protons
– Ca2+ Na+ K+
– Cl-
• First messenger: neurotransmitter
• Second messenger: other molecule
• Kinase: enzyme that adds phosphate (PO4)

18.
So Many Receptors!
Serotonin (5-HT):
1
2
3
4
5
6
7

19.
Family 1: Ionotropic
• Binding to receptor opens channel to let ions
in (aka: ligand gated ion receptors)

20.
Family 1: Ionotropic
• Binding to receptor opens channel to let ions
in (aka: ligand gated ion receptors)
0:40 – 6:20: http://www.youtube.com/watch?v=8jPH2pKzIDY

21.
Allosteric Modulation
• orthosteric: site where the neurotransmitter
(A) binds to a receptor
• allosteric: site where other molecule (B)
binds, has no independent effect

22.
Positive Allosteric Modulation
• A+B>A
• Example: Benzodiazepines
Stahl (2008). Essentials of Psychopharmacology, p. 144.

23.
Negative Allosteric Modulation
• A+B<A
• Example: clozapine
Stahl (2008). Essentials of Psychopharmacology, p. 144.

24.
Family 2: Metabotropic (2nd messenger)
• Steps:
• 1) Ligand binds receptor
• 2) G protein acts on enzyme
• 3) Enzyme regulates 2nd
messenger
• 4) 2nd messenger acts on
protein kinase
6:30-9:00 http://www.youtube.com/watch?v=8jPH2pKzIDY

25.
Family 2: Metabotropic (Channel)
• Steps:
• 1) Ligand binds receptor
• 2) G protein alters
channel
• 3) ions flow out of
neuron

26.
Receptor Families Compared
Ionotropic Metabotropic
(nACh, GABA-A, 5-HT3, NMDA) ( M1, D2, alpha1,2, GABA-B)
Subunits 4-5 1
Mechanism Simple: Channel opening Complex: G protein cascade
2nd messengers No Yes
Speed Fast (msec) Slow (hours – week)
Meyer & Quenzer (2005). p 73

27.
Family 3: Tyrosine Kinase
• Steps:
1) Ligand (BDNF) binds to Trk receptor
2) Trk receptors come together, and
phosphorylate each other

28.
So many potential drug targets!!!
Examples:
1) Tryptophan
6) Nicotine
10) MAO-I
11) SSRIs

29.
Current Targets of Psychotropic Drugs
• Metabotropic Receptors (30%)
• Transporters (30%)
• Ion Channels (30%)
• Enzymes (10%)
Stahl, S. (2008). Essential Psychopharmacology. p. 92.

30.
General Adage
• “every drug acts on at least two receptors, the
one you know about and the one you don’t”
• Solution:
– Pharmacological: use selective agonists, problem:
not available?
– Knock-out: generate mouse, problem:
developmental compensation
• Temporally specific: gene inactivated at specific time
(adulthood)
• Tissue specific: gene inactivated in specific region/area