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Neuroscience, 4e Presentation Transcript

  • 1. Neurotransmitters and Receptors March 18, 2010
  • 2. Neurotransmitters
    • Classes of Neurotransmitters
      • Small Molecules
        • Amino Acids
        • Biogenic Amines
        • Acetylcholine
        • Purines
      • Peptides
      • Unconventional
  • 3. Small-molecule Neurotransmitters
  • 4. Small-molecule Neurotransmitters
    • Biogenic Amines
  • 5. Peptide Neurotransmitters
  • 6. Neurotransmitters
    • Synthesis
      • Precursors
      • Rate limiting steps
      • Location (Cell types)
    • Inactivation
    • Post-synaptic receptors
      • Structure
      • Subtypes
  • 7. Neurotransmitter Receptors
    • Ionotropic – This week
      • Electrical response to neurotransmitter binding
      • Large, 4-5 subunit protein forms channel
      • Impermeable in the absence of transmitter
      • Rapid onset, rapidly reversible
    • Metabotropic – Next week
      • G protein coupled receptor (GPCR)
      • Single polypeptide receptor
      • Slow onset, long duration
  • 8. Terminology
    • Agonist
      • Molecule that binds to and activates receptor or channel
    • Antagonist
      • Molecule that binds to and inhibits receptor or channel
    • Desensitization
      • Transition to closed state in presence of neurotransmitter
      • Limits ion influx
    • Allosteric binding sites
      • Different than binding site of ligand
      • Modulates receptor or channel properties
  • 9. Acetylcholine
    • Synthesis
      • Acetyl from acetyl coA is transferred to choline by choline acetyl transferase (ChAT)
        • ChAT is rate limiting step
      • Acetyl coA precursor
        • Derived from pyruvate (glucose metabolism)
        • Must exit mitochondria to gain access to ChAT
      • High affinity Na+/Choline transporter moves choline into neuron
  • 10. Acetylcholine
    • Packaging
      • Vesicular cholinergic transporter
      • Moves 10,000 molecules into vesicles
    • Inactivation
      • Primarily enyzmatic by acetylcholinesterase (AChE) in synaptic cleft
        • 5000 molecules/sec
      • Choline is conserved by re-uptake
  • 11. Acetylcholine in Cholinergic Nerve Terminals
  • 12. Clinical Applications
    • Nerve gas and organophosphate insecticides target AChE
      • Removal of inactivation causes muscle defibrillation and then inactivation of muscle
    • Neostigmine, inhibits AChE which increases ACh in synapse
      • Compensates for decreased Ach receptors due to auto-antibodies in Myasthenia gravis
  • 13. Myasthenia Gravis
    • End-plate potentials are smaller
    • Improved with neostigmine
  • 14. Neurotoxins that Act on Postsynaptic Receptors
    • Causing Paralysis:
      • Bungarotoxin
        • From Bungarus multicinctus
        • High affinity and specificity for nAChR
        • Used to purify receptor
      • Curare
        • Turbocurarine
        • Used on arrow tips by South American Indians
        • From Chondodendron tomentosum
  • 15. Neurotoxins that Act on Postsynaptic Receptors
    • Plant alkaloids
      • Nicotinia tabacum
        • Activates Nicotinic AChR
      • Muscarine
        • Poisonous red mushroom, Amanita Muscaria
        • Activates muscarinic AChR
      • Stimulants, producing nausea, vomiting, mental confusion
  • 16. Nicotinic Acetylcholine Receptor Structure
    • 5 subunits form functional channel
      • 2  subunits
        • ACh binding site
      • 3 other subunits
        • In neurons, 3  subunits
        • In muscle, combination of  subunits
    • Each subunit has 4 transmembrane domains
  • 17. Structure of the nACh receptor/channel
    • Long extracellular amino terminal has ACh binding site
      • Pore formed by 2 nd TM domain
      • 0.6 nm diameter pore opening
  • 18. The structure of the nACh receptor/channel
  • 19. Receptor Types Ionotropic Metabotropic
  • 20. Structure of Ligand-gated Receptor Channels
    • Five subunits
      • nAChR
      • GABA A
      • Glycine
      • Serotonin
    • Four subunits
      • Glutamate Receptors
  • 21. Structure of Ligand-gated Receptor Channels
    • Some have four TM domains
    • Some have three TM domains and a pore loop
  • 22. Subunit Subtypes of Ligand-gated receptors Glutamate GABA A
  • 23. Structure of Metabotropic Receptors
    • Seven TM domains
    • Single subunit
    • Intracellular segment and 3-4 loop binds to GTP binding protein
    • Extracellular loops 2-3 and 6-7 bind to neurotransmitter
  • 24. Subtypes of Metabotropic Receptors
    • All but biogenic amines have ionotropic receptors
    • Most will be discussed next week
    ACh
  • 25. Amino Acids
    • Excitatory
      • Glutamate
      • Aspartate
    • Inhibitory
      •  amino butyric acid (GABA)
      • glycine
    • Major neurotransmitters in CNS
  • 26. Amino Acid Transmitters
    • Synthesis
      • Derived from glucose metabolism
      •  -keto glutarate is formed by Tricarboxylic acid cycle
      • Transaminated to glutamate by GABA  oxoglutarate transaminase (GABA-T)
      • Glutamic acid decarboxylase (GAD) forms GABA from glutamate
    • Alternative Synthesis
      • Glutamate is formed directly from glutamine
        • Glutamine produced in glia, then transported into nerve terminals
  • 27. Amino Acid Transmitters
    • Vesicular Storage
      • Vesicular Glutamate transporter
      • GABA vesicular transporter
    • Inactivation is via re-uptake by glia and neurons
      • 3 types of GABA transporters (GAT)
      • Excitatory amino acid transporters for glutamate
        • Glia re-synthesize glutamine from glutamate
  • 28. Glutamate Synthesis and Inactivation
  • 29. Glutamatergic Neurons
    • Ubiquitous, excitatory transmitter
      • Pyramidal neurons of cortex and hippocampus
      • Granule cells of cerebellum
      • Thalamus
    • Difficult to distinguish glutamate from aspartate
  • 30. Glutamate Receptor Subtypes and Agonists
    • All have four subunits per channel
    • Subtypes distinguished by affinity of agonist
    • All have reversal potential of 0 mV
  • 31. NMDA type Glutamate Receptors
    • Glycine is co-agonist
    • Magnesium blocks pore unless depolarized
    • Calcium permeates channel
  • 32. NMDA type Glutamate Receptors
    • Mg ++ blocks current below -40 mV
      • Without Mg ++ , linear IV curve
    • Glycine required for current
  • 33. NMDA and AMPA/kainate Receptors
    • AMPA has linear IV curve
    • AMPA is not permeable to calcium
    • AMPA response is faster than NMDA
  • 34. Drugs Acting at Glutamate Receptors
    • NMDA Receptor
      • AP5 and AP7 bind to and block glutamate site
        • Hallucinogenic
      • Open channel blocker (Allosteric)
        • MK801 (dizocilpine)
        • Phencyclidine (PCP)
        • Become trapped when closed, difficult to wash out
    • AMPA receptor
      • DNQX and CNQX used experimentally
  • 35. Excitatotoxicity
    • Caused by abnormally high levels of glutamate
      • Dendrites of target neurons are swollen
      • Effect blocked by glutamate antagonists
    • Observed after ischemia, e.g. due to stroke
      • Clinical trials using glutamate antagonists were disappointing
        • Treatment may occur too late
  • 36. Synthesis, release, reuptake of GABA
    • Pyridoxal Phosphate derived from vitamin B6
  • 37. Synthesis, release, reuptake of glycine
  • 38. GABAergic Neurons
    • Local circuit interneurons
      • Cortex
      • Hippocampus
      • Striatum
    • Projection neurons
      • Cerebellar Purkinje Cells
      • Spiny projection neurons of striatum
      • Globus pallidus and Substantia Nigra pars Reticulata
    • Glycine
      • Predominant inhibitory transmitter in spinal cord
  • 39. Ionotropic GABA A receptors
    • Chloride permeable channels
      • Chloride influx produces IPSP
      • Stop firing
      • Decrease firing rate
  • 40. Drugs acting on GABA A Receptors
    • Benzodiazepines
      • Valium, Librium
      • Enhances GABA currents
    • Barbiturates
      • Phenobarbital – anti-epileptic
      • Pentobarbital – anesthetic
    • Steroid metabolites of testosterone, corticosterone, progesterone
  • 41. Drugs acting on GABA and Glycine Receptors
    • Strychnine
      • From seeds of Strycnos nux-vomica
      • Blocks glycine receptors
      • Overexcitation of brainstem and cord
      • Seizures
    • Picrotoxin
      • From Anamerta cocculs
      • Blocks GABA A channels
      • Used experimentally
  • 42. Ionotropic GABA A receptors
    • Two GABA binding sites
    • Two  subunits
  • 43. Excitatory Actions of GABA A in Developing Brain
    • Developing brain has higher K/Na/Cl transporter
      • Higher intracellular chloride
    • Older brains have higher K/Cl transporters
      • Lower intracellular chloride
  • 44. Excitatory Actions of GABA A in Developing Brain
    • Developing brain:
      • E Cl is greater than AP threshold
      • GABA is Excitatory
    • Older brain:
      • E Cl is lower than AP threshold
      • GABA is Inhibitory
  • 45. Catecholamines
    • Molecule with Catechol nucleus
      • Benzene Ring with 2 adjacent hydroxyl substitutions plus amine group
    • Types
      • Dopamine (DA)
      • Epinephrine (Epi or Adrenaline)
      • Norepinephrine (NE or Noradrenaline)
    • Act as neurotransmitters in CNS, PNS and hormonal function
  • 46. Catecholamine Synthesis
    • Precursor
      • Tyrosine
        • General large amino acid transporter; energy dependent mechanism to cross BBB
    • Rate limiting step
      • Tyrosine Hydroxylase
      • Converts tyrosine to DOPA
  • 47. Biosynthetic Pathway for the Catecholamines
    • DOPA decarboxylase has extremely rapid action
      • L-DOPA crosses BBB, rapidly converted to DA
      • L-DOPA is treatment for Parkinson’s
  • 48. Biosynthetic Pathway for the Catecholamines
    • Dopamine  hydroxylase only in NE producing neurons
    • Phenylethanolamine N-methyltransferase (PNMT) on in Epi producing neurons
  • 49. Catecholamine Storage
    • Vesicular Monoamine Transporter (VMAT1 and 2)
      • Also used for serotonin
      • Will transport other amines, including amphetamines
    • Blocked by Reserpine
      • Depletes stores of serotonin, DA, NE
      • Used to treat psychosis of Schizophrenia
  • 50. Catecholamine Inactivation
    • Dopamine Transporter (DAT)
      • Binds to dopamine, transports it into pre-synaptic terminal for re-use
      • Methylphenidate inhibits the DAT
      • Cocaine inhibits the DAT
    • Norepinephrine Transporter (NET)
      • Binds to NE and dopamine, transports them into pre-synaptic terminal for re-use
      • Tricyclic anti-depressants inhibit the NET
  • 51. Catecholamine Inactivation
    • Degradation
      • Monoamine oxidase (MAO)
        • After re-uptake
        • In mitochondria
      • Catechol-o-methyltransferase (COMT)
        • In cytoplasm
      • Both are targets of anti-depressant drugs
  • 52. Dopamine Neurons and their Projections
    • Substantia Nigra pars Compacta projects strongly to striatum
      • Degenerates in Parkinson’s
    • VTA projects strongly to Nucleus Accumbans and Prefrontal Cortex
    • Role in reward and addiction
  • 53. Norepinephrine Neurons and their Projections
    • Locus Coeruleus produces NE
    • Wide and diffuse projection
    • Role in
      • attention
      • Sleep-wake cycles
  • 54. Epinephrine Neurons and their Projections
    • Brain: medullary epinephrine neurons
      • Project to thalamus, hypothalamus, medulla
    • Periphery: adrenal medulla
      • Part of adrenal gland
      • Endocrine organ near kidneys
      • Fight or Flight
  • 55. Synthesis of Histamine
    • Produced by mast cells in the blood stream
      • Role in inflammation
    • Loaded into vesicles with VMAT
    • Degradation by histamine methyltransferase and MAO
  • 56. Histamine Neurons and their Projections
    • Role in arousal and attention
    • Reactivity of vestibular system
  • 57. Histamine Receptors
    • Three types (metabotropic)
      • Antagonists to H1 prevent motion sickness
      • Antagonists to H2 reduce gastric acid secretion
      • Diphenhydramine crosses BBB, acts as sedative
  • 58. Synthesis of Serotonin
    • Indoleamine
      • Indole structure similar to LSD
    • Precursor
      • Tryptophan
    • Rate limiting step
      • Tryptophan hydroxylase
  • 59. Serotonin Receptors and Inactivation
    • Serotonin Transporter (SERT)
      • Binds to serotonin, transports it into pre-synaptic terminal for re-use
      • Inhibited by Fluoxetine (Prozac)
    • Loaded into vesicles by VMAT
    • Fenfluramine, MDMA, ecstatsy
      • Inhibits both VMAT and SERT
  • 60. Serotonin Neurons and their Projections
    • Regulates sleep-wake cycles
    • Implicated in psychiatric disorders
    • Only one ionotropic receptor
      • 5-HT 3
      • Non-selective cation channel
      • E R = 0 mV
  • 61. Purines
    • Two main types
      • ATP: co-released by all vesicles
      • Adenosine: generated from ATP by extracellular enzymes
    • Three classes of receptors
      • Ionotropic
        • Nonselective cation channel
        • Two transmembrane domain
      • Metabotropic
        • Adenosine preferring
          • blocked by caffeine and theophylline
        • ATP preferring
  • 62. Neuropeptides
    • Pre-propeptides synthesized in soma (rough ER) by protein translation
    • Propeptide created by cleavage of signal sequence (in RER), secreted
    • Peptide created by processing in Golgi
      • Proteolytic cleavage
      • Glycosylation, phosphorylation, disulfide bond formation
      • Packaging into vesicles
  • 63. Proteolytic processing of pre-proenkephalin A
    • Large propeptides can be cleaved into multiple active peptides
  • 64. Proteolytic processing of pre-proopiomelanocortin
    • All act on G protein coupled receptors
  • 65. Neuropeptides contain 3 to 36 amino acids
    • Five categories
      • Brain-gut: found in brain and gut
      • Opioid: morphine-like activity
  • 66. Neuropeptides contain 3 to 36 amino acids
    • Five categories
      • Hypothalamic: release pituitary peptide hormones
  • 67. Opioid Receptors
    • Distributed throughout the brain
      • Co-localized with GABA and 5HT receptors
      • Analgesic
      • Depressant
      • Behaviors: sexual attraction and aggression/submission
    • Involved in addiction
  • 68.  
  • 69. Unconventional Neurotransmitters
    • Why unconventional?
      • Not stored in vesicles
      • Released from post-synaptic terminals
      • Act on pre-synaptic terminals
    • Two classes
      • Endocannabinoids
      • NO
  • 70. Endocannabinoid Molecules
    • Phosphatidyl-ethanolamine is a membrane phospholipid
  • 71. Endocannabinoid Molecules
    • Phosphatidylinositol is membrane phospholipid
  • 72. Endocannabinoid Molecules
    • Unsaturated fatty acid with polar head group
    • Production stimulated by rise in calcium
    • Diffuse from post-synaptic neuron to pre-synaptic terminal to bind to CB1 receptors
    • Inhibits release of GABA neurotransmitter
    • Two inhibitors
  • 73. Endocannabinoid-mediated inhibition of GABA
    • Depolarization leads to calcium influx, endocannabinoid production, inhibition of GABA release, smaller IPSC
      • IPSC inhibition is blocked by rimonabant
  • 74. Endocannabinoid Receptors
    • Receptors
      • Cortex, cerebellum, hippocampus
      • Enriched caudate putamen and substrantia nigra
        • Brain regions involved in addiction
  • 75. Marijuana and the Brain
    • Marijuana acts on endocannabinoid receptors
      • Active ingredient is  9 -tetrahydrocannabinol
  • 76. Synthesis, release, and termination of NO
    • NO synthase produces nitric oxide
      • NO synthase activated by calcium-calmodulin
  • 77. Synthesis, release, and termination of NO
    • NO freely diffuses through membranes to activate pre- and post-synaptic terminals
      • Spontaneously decays within seconds
  • 78.