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Neurocommunication

   Brian J. Piper, Ph.D.
Terminology
• Neurotransmitter: chemical that is released in
  the brain and has an effect on a local target
• Hormone: chemical that is released into
  bloodstream that has an effect on a distant
  target
Goals
• Neurotransmission
  – History
  – Onset: Neurotransmitter release (classical and
    non-classical)
  – Offset: autoreceptors, transporters, enzymes
  – Receptor Families
• Endocrine
History: Golgi vs. Cajal
• Italian physician
• Reticulum theory
• Silver stain




                          Camillo Golgi (1843-1926)
Controversy: Golgi vs. Cajal
                          • Santiogo Ramon y Cajal
                               – Neuroanatomist
                               – Used Golgi’s technique
                               – Neuron theory




1852-1934



                Chicken cerebellum
Neural Communication
 The body’s information system is built from
billions of interconnected cells called neurons.
   Communication between neurons is both
             electrical and chemical.
Otto Loewi
• Discovered “Vagusstoff” later
  known as acetylcholine
• “father of neuroscience”
• Nobel Prize 1936
What are amino acids?
• Amine (NH2) + Carboxyl ( -COOH)
• 20 total, 9 essential




                    tyrosine        Tryptophan
More terminology
• 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
More terminology
• Peptides: short (<50) strings of amino acids,
  Valine-Glycine-Serine-Alanine… e.g. NPY
More terminology
Proteins: longer strings of amino acids, have 3-D
structure, form receptors, transporters
Comparison
                     Peptide             Protein
Size (amino acids)   < 40                >40
Dimensions           1-D                 3-D
Complexity           Low                 High




                            Hemoglobin
“Typical” Synapse
Electron Microscope
• Beams of electrons are presented to a thin
  section, 50 pm (10-12) resolution
• Reveals different types of Synapses
Dendritic Spine
Axodendritic Synapse
Axosomatic Synapse
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”
Neurotransmitter Comparison
                Classical   Non-Classical
Discovery       1950’s      1980’s
Concentration   High        Low
#               Few         Many
Synthesis       Anywhere    Soma
Classical Neurotransmitters
• Monoamines: dopamine, norepinephrine,
  serotonin
• Acetylcholine (ACh)
• Amino Acids: glycine, GABA, Glutamate
Non-classical Neurotransmitters
• Peptides: Corticotropin-releasing factor (CRF),
  endorphins
• Lipids: Anandamide
• Gases: Nitric Oxide
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.
Axon Terminal
Brakes II
• Autoreceptors: this receptor (“auto” = “self”)
  can act to inhibit further neurotransmitter
  release
  – Terminal (axon) autoreceptors: inhibit
    neurotransmitter release
  – Somatodendritic autoreceptors: reduce rate of
    action potentials
Brakes I
• Enzyme: A + B __ENZ____> AB
• Enzyme: CD    __ENZ____> C + D
Transporters
• Proteins that move molecule from one place
  to another, examples:
  – SERT: serotonin transporter
  – NET: norepinephrine transporter
  – DAT: dopamine transporter



                            Inside
                            ----------------------------------------------------------------------
                            Outside
Neuropharmacology: Neurotransmission
Post-synaptic
• 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)
Types of Receptors
So Many Receptors!
           Serotonin (5-HT):
           1
           2
           3
           4
           5
           6
           7
Family 1: Ionotropic
• Binding to receptor opens channel to let ions
  in (aka: ligand gated ion receptors)
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
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
Family 2: Metabotropic (Channel)
• Steps:
• 1) Ligand binds receptor
• 2) G protein alters
  channel
• 3) ions flow out of
   neuron
Receptor Families Compared
                 Ionotropic                 Metabotropic
Subunits         4-5                        1
Mechanism        Simple: Channel opening    Complex: G protein cascade
2nd messengers   No                         Yes
Speed            Fast                       Slow




                                           Meyer & Quenzer (2005). p 73
Family 3: Tyrosine Kinase
• Steps:
1) Ligand (BDNF) binds to Trk receptor
2) Trk receptors come together, and
phosphorylate each other
Neuropharmacology: Neurotransmission
So many drug targets!!!
                  Examples:
                  1) Tryptophan
                  6) Nicotine
                  10) MAO-I
                  11) SSRIs
Endocrine System
Gland      Hormone (Function)
Pineal     Melatonin (light-dark rhythm)
Thyroid    T3/T4 (energy)
Adrenal    Cortisol (stress)
Pancreas   Insulin (glucose)
Ovaries    Estrogens (2nd sex characteristics)
Testes     Androgens (2nd sex characteristics)
Example
    • Rats that received ecstasy (MDMA) during
      adolescence were more sensitive to a 5-HT2
      agonist when adults




Biezonski et al. (2009). Brain Research, 1252, 87-93.
Reference

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Neuropharmacology: Neurotransmission

  • 1. Neurocommunication Brian J. Piper, Ph.D.
  • 2. Terminology • Neurotransmitter: chemical that is released in the brain and has an effect on a local target • Hormone: chemical that is released into bloodstream that has an effect on a distant target
  • 3. Goals • Neurotransmission – History – Onset: Neurotransmitter release (classical and non-classical) – Offset: autoreceptors, transporters, enzymes – Receptor Families • Endocrine
  • 4. History: Golgi vs. Cajal • Italian physician • Reticulum theory • Silver stain Camillo Golgi (1843-1926)
  • 5. Controversy: Golgi vs. Cajal • Santiogo Ramon y Cajal – Neuroanatomist – Used Golgi’s technique – Neuron theory 1852-1934 Chicken cerebellum
  • 6. Neural Communication The body’s information system is built from billions of interconnected cells called neurons. Communication between neurons is both electrical and chemical.
  • 7. Otto Loewi • Discovered “Vagusstoff” later known as acetylcholine • “father of neuroscience” • Nobel Prize 1936
  • 8. What are amino acids? • Amine (NH2) + Carboxyl ( -COOH) • 20 total, 9 essential tyrosine Tryptophan
  • 9. More terminology • 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
  • 10. More terminology • Peptides: short (<50) strings of amino acids, Valine-Glycine-Serine-Alanine… e.g. NPY
  • 11. More terminology Proteins: longer strings of amino acids, have 3-D structure, form receptors, transporters
  • 12. Comparison Peptide Protein Size (amino acids) < 40 >40 Dimensions 1-D 3-D Complexity Low High Hemoglobin
  • 14. Electron Microscope • Beams of electrons are presented to a thin section, 50 pm (10-12) resolution • Reveals different types of Synapses
  • 18. 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”
  • 19. Neurotransmitter Comparison Classical Non-Classical Discovery 1950’s 1980’s Concentration High Low # Few Many Synthesis Anywhere Soma
  • 20. Classical Neurotransmitters • Monoamines: dopamine, norepinephrine, serotonin • Acetylcholine (ACh) • Amino Acids: glycine, GABA, Glutamate
  • 21. Non-classical Neurotransmitters • Peptides: Corticotropin-releasing factor (CRF), endorphins • Lipids: Anandamide • Gases: Nitric Oxide
  • 22. 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.
  • 24. Brakes II • Autoreceptors: this receptor (“auto” = “self”) can act to inhibit further neurotransmitter release – Terminal (axon) autoreceptors: inhibit neurotransmitter release – Somatodendritic autoreceptors: reduce rate of action potentials
  • 25. Brakes I • Enzyme: A + B __ENZ____> AB • Enzyme: CD __ENZ____> C + D
  • 26. Transporters • Proteins that move molecule from one place to another, examples: – SERT: serotonin transporter – NET: norepinephrine transporter – DAT: dopamine transporter Inside ---------------------------------------------------------------------- Outside
  • 28. Post-synaptic • 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)
  • 30. So Many Receptors! Serotonin (5-HT): 1 2 3 4 5 6 7
  • 31. Family 1: Ionotropic • Binding to receptor opens channel to let ions in (aka: ligand gated ion receptors)
  • 32. 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
  • 33. 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
  • 34. Family 2: Metabotropic (Channel) • Steps: • 1) Ligand binds receptor • 2) G protein alters channel • 3) ions flow out of neuron
  • 35. Receptor Families Compared Ionotropic Metabotropic Subunits 4-5 1 Mechanism Simple: Channel opening Complex: G protein cascade 2nd messengers No Yes Speed Fast Slow Meyer & Quenzer (2005). p 73
  • 36. Family 3: Tyrosine Kinase • Steps: 1) Ligand (BDNF) binds to Trk receptor 2) Trk receptors come together, and phosphorylate each other
  • 38. So many drug targets!!! Examples: 1) Tryptophan 6) Nicotine 10) MAO-I 11) SSRIs
  • 39. Endocrine System Gland Hormone (Function) Pineal Melatonin (light-dark rhythm) Thyroid T3/T4 (energy) Adrenal Cortisol (stress) Pancreas Insulin (glucose) Ovaries Estrogens (2nd sex characteristics) Testes Androgens (2nd sex characteristics)
  • 40. Example • Rats that received ecstasy (MDMA) during adolescence were more sensitive to a 5-HT2 agonist when adults Biezonski et al. (2009). Brain Research, 1252, 87-93.