9. “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
10. 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
20. 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)
22. Family 1: Ionotropic
• Binding to receptor opens channel to let ions
in (aka: ligand gated ion receptors)
23. 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
24. Allosteric Modulation
• orthosteric: site where the neurotransmitter
(A) binds to a receptor
• allosteric: site where other molecule (B)
binds, has no independent effect
25. Positive Allosteric Modulation
• A+B>A
• Example: Benzodiazepines
Stahl (2008). Essentials of Psychopharmacology, p. 144.
27. 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
28. Family 2: Metabotropic (Channel)
• Steps:
• 1) Ligand binds receptor
• 2) G protein alters
channel
• 3) ions flow out of
neuron
29. 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
30. Family 3: Tyrosine Kinase
• Steps:
1) Ligand (BDNF) binds to Trk receptor
2) Trk receptors come together, and
phosphorylate each other
31.
32. So many potential drug targets!!!
Examples:
1) Tryptophan
6) Nicotine
10) MAO-I
11) SSRIs
33. Current Targets of Psychotropic Drugs
• Metabotropic Receptors (30%)
• Transporters (30%)
• Ion Channels (30%)
• Enzymes (10%)
Stahl, S. (2008). Essential Psychopharmacology. p. 92.
34. 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