Neuroscience, 4e

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  • Neuroscience, 4e

    1. 1. Neurotransmitters and Receptors March 18, 2010
    2. 2. Neurotransmitters Classes of Neurotransmitters • Small Molecules  Amino Acids  Biogenic Amines  Acetylcholine  Purines • Peptides • Unconventional
    3. 3. Small-molecule Neurotransmitters
    4. 4. Small-molecule Neurotransmitters Biogenic Amines
    5. 5. Peptide Neurotransmitters
    6. 6. Neurotransmitters Synthesis • Precursors • Rate limiting steps • Location (Cell types) Inactivation Post-synaptic receptors • Structure • Subtypes
    7. 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. 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. 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. 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. 11. Acetylcholine in Cholinergic Nerve Terminals
    12. 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. 13. Myasthenia Gravis End-plate potentials are smaller Improved with neostigmine
    14. 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. 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. 16. Nicotinic Acetylcholine Receptor Structure 5 subunits form functional channel • 2 α subunits  ACh binding site • 3 other subunits  In neurons, 3 β subunits  In muscle, combination of β, γ, δ, ε subunits Each subunit has 4 transmembrane domains
    17. 17. Structure of the nACh receptor/channel Long extracellular amino terminal has ACh binding site • Pore formed by 2nd TM domain • 0.6 nm diameter pore opening
    18. 18. The structure of the nACh receptor/channel
    19. 19. Receptor Types Ionotropic Metabotropic
    20. 20. Structure of Ligand-gated Receptor Channels Five subunits • nAChR • GABAA • Glycine • Serotonin Four subunits • Glutamate Receptors
    21. 21. Structure of Ligand-gated Receptor Channels  Some have four TM domains  Some have three TM domains and a pore loop
    22. 22. Subunit Subtypes of Ligand-gated receptors Glutamate GABAA
    23. 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. 24. Subtypes of Metabotropic Receptors All but biogenic amines have ionotropic receptors Most will be discussed next week ACh
    25. 25. Amino Acids Excitatory • Glutamate • Aspartate Inhibitory • γ amino butyric acid (GABA) • glycine Major neurotransmitters in CNS
    26. 26. Amino Acid Transmitters  Synthesis • Derived from glucose metabolism • α-keto glutarate is formed by Tricarboxylic acid cycle • Transaminated to glutamate by GABA α 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. 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. 28. Glutamate Synthesis and Inactivation
    29. 29. Glutamatergic Neurons Ubiquitous, excitatory transmitter • Pyramidal neurons of cortex and hippocampus • Granule cells of cerebellum • Thalamus Difficult to distinguish glutamate from aspartate
    30. 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. 31. NMDA type Glutamate Receptors Glycine is co-agonist Magnesium blocks pore unless depolarized Calcium permeates channel
    32. 32. NMDA type Glutamate Receptors Mg++ blocks current below -40 mV • Without Mg++ , linear IV curve Glycine required for current
    33. 33. NMDA and AMPA/kainate Receptors AMPA has linear IV curve AMPA is not permeable to calcium AMPA response is faster than NMDA
    34. 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. 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. 36. Synthesis, release, reuptake of GABA Pyridoxal Phosphate derived from vitamin B6
    37. 37. Synthesis, release, reuptake of glycine
    38. 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. 39. Ionotropic GABAA receptors Chloride permeable channels • Chloride influx produces IPSP • Stop firing • Decrease firing rate
    40. 40. Drugs acting on GABAA Receptors Benzodiazepines • Valium, Librium • Enhances GABA currents Barbiturates • Phenobarbital – anti-epileptic • Pentobarbital – anesthetic Steroid metabolites of testosterone, corticosterone, progesterone
    41. 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 GABAA channels • Used experimentally
    42. 42. Ionotropic GABAA receptors Two GABA binding sites Two α subunits
    43. 43. Excitatory Actions of GABAA 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. 44. Excitatory Actions of GABAA in Developing Brain Developing brain: • ECl is greater than AP threshold • GABA is Excitatory Older brain: • ECl is lower than AP threshold • GABA is Inhibitory
    45. 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. 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. 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. 48. Biosynthetic Pathway for the Catecholamines Dopamine β hydroxylase only in NE producing neurons Phenylethanolamine N- methyltransferase (PNMT) on in Epi producing neurons
    49. 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. 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. 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. 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. 53. Norepinephrine Neurons and their Projections Locus Coeruleus produces NE Wide and diffuse projection Role in • attention • Sleep-wake cycles
    54. 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. 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. 56. Histamine Neurons and their Projections Role in arousal and attention Reactivity of vestibular system
    57. 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. 58. Synthesis of Serotonin Indoleamine • Indole structure similar to LSD Precursor • Tryptophan Rate limiting step • Tryptophan hydroxylase
    59. 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. 60. Serotonin Neurons and their Projections Regulates sleep-wake cycles Implicated in psychiatric disorders  Only one ionotropic receptor • 5-HT3 • Non-selective cation channel • ER = 0 mV
    61. 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. 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. 63. Proteolytic processing of pre-proenkephalin A Large propeptides can be cleaved into multiple active peptides
    64. 64. Proteolytic processing of pre- proopiomelanocortin All act on G protein coupled receptors
    65. 65. Neuropeptides contain 3 to 36 amino acids Five categories • Brain-gut: found in brain and gut • Opioid: morphine-like activity
    66. 66. Neuropeptides contain 3 to 36 amino acids Five categories • Hypothalamic: release pituitary peptide hormones
    67. 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. 68. Unconventional Neurotransmitters Why unconventional? • Not stored in vesicles • Released from post-synaptic terminals • Act on pre-synaptic terminals Two classes • Endocannabinoids • NO
    69. 69. Endocannabinoid Molecules Phosphatidyl- ethanolamine is a membrane phospholipid
    70. 70. Endocannabinoid Molecules Phosphatidylinositol is membrane phospholipid
    71. 71. 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
    72. 72. Endocannabinoid-mediated inhibition of GABA Depolarization leads to calcium influx, endocannabinoid production, inhibition of GABA release, smaller IPSC • IPSC inhibition is blocked by rimonabant
    73. 73. Endocannabinoid Receptors  Receptors • Cortex, cerebellum, hippocampus • Enriched caudate putamen and substrantia nigra  Brain regions involved in addiction
    74. 74. Marijuana and the Brain Marijuana acts on endocannabinoid receptors • Active ingredient is ∆9 - tetrahydrocannabinol
    75. 75. Synthesis, release, and termination of NO NO synthase produces nitric oxide • NO synthase activated by calcium- calmodulin
    76. 76. Synthesis, release, and termination of NO NO freely diffuses through membranes to activate pre- and post-synaptic terminals • Spontaneously decays within seconds

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