Neurotransmission

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This presentation was delivered to 1st year pharmacy students. It is intended as a broad overview of neurochemistry.

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Neurotransmission

  1. 1. NeurotransmissionBrian J. Piper, Ph.D., M.S.
  2. 2. Goals• Introduction to neurocommunication• Families of receptors (2)• Inactivation of neurotransmission (3)
  3. 3. Otto Loewi• Discovered “Vagusstoff” later known as acetylcholine• “father of neuroscience”• Nobel Prize 1936
  4. 4. Types of Synapses• Electron Microscope: Beams of electrons are presented to a thin section, 50 pm (10-12) resolution
  5. 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. 6. Classical Neurotransmitters• Amino Acids: GABA, Glutamate• Monoamines: dopamine, norepinephrine, serotonin• Acetylcholine (ACh)
  7. 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. 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. 9. Non-classical Neurotransmitters• Peptides: Corticotropin-releasing factor (CRF), endorphins• Lipids: Anandamide• Gases: Nitric Oxide
  10. 10. Neurotransmitter Comparison Classical Non-ClassicalDiscovery 1950’s 1980’sConcentration High Low# Few ManySynthesis Anywhere Soma
  11. 11. Co-Transmitters Amine/Amino Acid Peptide Dopamine Cholecystokinin (CCK) Norepinephrine enkephalin Epinephrine neurotensin Serotonin substance P Acetylcholine somatostatin Gamma aminobutyric acid (GABA) motilinStahl, S. (2000). Essential Psychopharmacology, p. 20.
  12. 12. Axon Terminal
  13. 13. Brakes I: Inactivation of Neurotransmitter:• Enzyme: A + B __ENZ____> AB• Enzyme: CD __ENZ____> C + D
  14. 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. 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. 16. Brakes III: Transporters• Structure: 12 transmembrane regions• What happens if you inhibit brakes?
  17. 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. 18. So Many Receptors! Serotonin (5-HT): 1 2 3 4 5 6 7
  19. 19. Family 1: Ionotropic• Binding to receptor opens channel to let ions in (aka: ligand gated ion receptors)
  20. 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. 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. 22. Positive Allosteric Modulation • A+B>A • Example: BenzodiazepinesStahl (2008). Essentials of Psychopharmacology, p. 144.
  23. 23. Negative Allosteric Modulation • A+B<A • Example: clozapineStahl (2008). Essentials of Psychopharmacology, p. 144.
  24. 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. 25. Family 2: Metabotropic (Channel)• Steps:• 1) Ligand binds receptor• 2) G protein alters channel• 3) ions flow out of neuron
  26. 26. Receptor Families Compared Ionotropic Metabotropic (nACh, GABA-A, 5-HT3, NMDA) ( M1, D2, alpha1,2, GABA-B)Subunits 4-5 1Mechanism Simple: Channel opening Complex: G protein cascade2nd messengers No YesSpeed Fast (msec) Slow (hours – week) Meyer & Quenzer (2005). p 73
  27. 27. Family 3: Tyrosine Kinase• Steps:1) Ligand (BDNF) binds to Trk receptor2) Trk receptors come together, andphosphorylate each other
  28. 28. So many potential drug targets!!! Examples: 1) Tryptophan 6) Nicotine 10) MAO-I 11) SSRIs
  29. 29. Current Targets of Psychotropic Drugs • Metabotropic Receptors (30%) • Transporters (30%) • Ion Channels (30%) • Enzymes (10%)Stahl, S. (2008). Essential Psychopharmacology. p. 92.
  30. 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

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