Neurotransmitters

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Neurotransmitters

  1. 1. Neurotransmitters
  2. 2. Discovery of Neurotransmitters <ul><li>Otto Loewi, an Austrian scientist, discovered the first neurotransmitter in 1921. </li></ul><ul><li>He used two frog hearts. </li></ul><ul><li>One heart was still connected to the vagus nerve. </li></ul><ul><li>Heart #1 was placed in a chamber that was filled with saline. </li></ul><ul><li>This chamber was connected to a second chamber that contained heart #2. </li></ul><ul><li>Fluid from chamber #1 was allowed to flow into chamber #2. </li></ul>
  3. 3. Loewi’s Results <ul><li>Electrical stimulation of the vagus nerve attached to heart #1 caused heart #1 to slow down. </li></ul><ul><li>After a delay, heart #2 also slowed down. </li></ul><ul><li>Loewi hypothesized that electrical stimulation of the vagus nerve released a chemical into the fluid of chamber #1 that flowed into chamber #2. </li></ul><ul><li>He called this chemical &quot;Vagusstoff&quot;. </li></ul><ul><li>We now know this chemical as the neurotransmitter acetylcholine . </li></ul>
  4. 4. Otto Loewi’s Experiment
  5. 5. What is a Neurotransmitter? <ul><li>A substance that is released at a synapse by a neuron and that effects another cell, either a neuron or an effector organ, in a specialized manner </li></ul><ul><li>This seems clear, but application becomes fuzzy  </li></ul>
  6. 6. Neurotransmitter Criteria <ul><li>Chemical messengers must meet 4 criteria to be considered transmitters: </li></ul><ul><ul><li>It is synthesized by a neuron. </li></ul></ul><ul><ul><li>It is present in the presynaptic terminal and is released in amounts sufficient to exert a defined action on a postsynaptic neuron or effector organ. </li></ul></ul><ul><ul><li>When given as a drug, it mimics the action of naturally occurring transmitter in the body exactly. </li></ul></ul><ul><ul><li>A specific mechanism exists for removing it. </li></ul></ul>
  7. 7. Chemical Synaptic Transmission <ul><li>4 steps: </li></ul><ul><ul><li>Synthesis of transmitter </li></ul></ul><ul><ul><li>Storage & release of transmitter </li></ul></ul><ul><ul><li>Interaction of transmitter with receptor in postsynaptic membrane </li></ul></ul><ul><ul><li>Removal of transmitter from synaptic cleft </li></ul></ul>
  8. 8. Classifying Neurotransmitters <ul><li>Once divided into 2 classes: </li></ul><ul><ul><li>Cholinergic – use acetylcholine (ACh) </li></ul></ul><ul><ul><li>Adrenergic - use norepinephrine or epinephrine </li></ul></ul><ul><li>Now know there are many more types </li></ul><ul><li>2 large classes: </li></ul><ul><ul><li>Small molecules </li></ul></ul><ul><ul><li>Neuroactive peptides (short chains of amino acids) </li></ul></ul>
  9. 9. Manufacture of Large Molecule Transmitters <ul><li>Peptides </li></ul><ul><ul><li>Examples: substance P, somatostatin, leu-enkephalin, met-enkephalin, vasoactive intestinal polypeptide (VIP), bombesin </li></ul></ul><ul><li>Occurs in soma </li></ul><ul><li>Peptide synthesized in rough endoplasmic reticulum </li></ul><ul><li>Packaged in Golgi apparatus </li></ul><ul><li>Transported down axon to presynaptic ending of the axon terminal </li></ul><ul><ul><li>secretory vesicles transported down axon by orthograde axonal transport </li></ul></ul>
  10. 10. Manufacture of Small Molecule Transmitters <ul><li>Small molecule transmitters (amino acids and amines) </li></ul><ul><ul><li>Examples of amino acid neurotransmitters: gamma-amino butyric acid (GABA), glutamate (Glu), glycine (Gly) </li></ul></ul><ul><ul><li>Examples of amine neurotransmitters: acetylcholine (ACh), dopamine (DA), epinephrine, histamine, norepinephrine (NE), serotonin (5-HT) </li></ul></ul><ul><li>Occurs in axon terminal </li></ul><ul><li>Precursor molecule is transformed by synthetic enzyme into neurotransmitter molecule </li></ul><ul><li>Neurotransmitter molecules are gathered by transporter molecules and packaged in synaptic vesicles </li></ul>
  11. 11. Small Molecule Neurotransmitters <ul><li>Nine such substances are accepted as neurotransmitters: </li></ul><ul><ul><li>8 are amines </li></ul></ul><ul><ul><li>The non amine is ATP </li></ul></ul><ul><li>Synthesis of these neurotransmitters is catalyzed by enzymes </li></ul><ul><li>Acetylcholine - perhaps the most important small molecule transmitter </li></ul>
  12. 12. Acetylcholine <ul><li>Acetylcholine is the transmitter used by motor neurons of the spinal cord </li></ul><ul><li>Released at all vertebrate neuro-muscular junctions </li></ul><ul><li>Present in autonomic & parasympathetic neurons </li></ul><ul><li>Used in many brain synapses </li></ul>
  13. 13. Acetylcholine Synthesis <ul><li>Synthesis uses the enzyme choline acetyltransferase (ChAT) </li></ul><ul><li>Takes acetyl group from acetyl CoA in cytosol </li></ul><ul><li>Takes choline from extracellular fluid (rate limiting step) </li></ul>
  14. 14. Cholinergic Neurons <ul><li>Use acetylcholine as a neurotransmitter </li></ul><ul><li>2 types of receptors </li></ul><ul><ul><li>Nicotinic receptor - transmitter-gated ion channel </li></ul></ul><ul><ul><li>Muscarinic receptor - G-protein-coupled receptor using short-cut pathway to close potassium channel </li></ul></ul><ul><li>Removal </li></ul><ul><ul><li>degraded by acetylcholine esterase (AChE) </li></ul></ul><ul><ul><li>AChE is the target of many nerve gases and insecticides </li></ul></ul>
  15. 15. Biogenic Amine Transmitters <ul><li>The rest of the 8 amines </li></ul><ul><li>Includes serotonin & the catecholamines (dopamine, epinephrine & norepinephrine) </li></ul><ul><li>All catecholamines are synthesized from the amino acid, tyrosine. </li></ul><ul><ul><li>share a common biosynthetic pathway </li></ul></ul><ul><ul><li>pathway uses 5 enzymes </li></ul></ul>
  16. 16. Dopaminergic Neurons <ul><li>Use dopamine, norepinephrine, or epinephrine as neurotransmitters </li></ul><ul><li>Synthesis pathway: </li></ul><ul><ul><li>Tyrosine hydroxylase (TH) makes tyrosine into dopa </li></ul></ul><ul><ul><li>Dopa decarboxylase makes dopa into dopamine (DA) </li></ul></ul><ul><li>If the neuron is dopaminergic , the pathway stops here </li></ul>
  17. 17. Noradrenergic & Adrenergic Neurons <ul><li>The synthesis pathway continues from dopamine: </li></ul><ul><ul><li>Dopamine beta-hydroxylase (DBH) makes dopamine into norepinephrine </li></ul></ul><ul><li>If the neuron is noradrenergic , the pathway stops here, </li></ul><ul><li>Or the pathway can continue: </li></ul><ul><ul><li>Phentolamine N-methyltransferase (PNMT) makes norepinephrine into epinephrine </li></ul></ul><ul><li>If the neuron is adrenergic , the pathway goes the whole way to this point </li></ul>
  18. 18. Summary of Catecholamine Synthesis <ul><li>All catecholamines have a catechol nucleus & a 3,4-dihydroylated benzene ring </li></ul><ul><li>The 1st enzyme, tyrosine hydroxylase, converts tyrosine to L-dihydroxyphenylalanine (L-DOPA) </li></ul><ul><li>L-DOPA is a precursor for all catecholamines </li></ul><ul><li>The 2nd step converts L-DOPA to dopamine & CO 2 </li></ul><ul><li>The 3rd step converts dopamine to norepinephrine </li></ul><ul><li>The 4 th step converts norepinephrine to epinephrine </li></ul>
  19. 19. Catecholamine Synthesis
  20. 20. Norepinephrine <ul><li>In the CNS, norepinephrine is used by neurons of the locus coeruleus, a nucleus of the brainstem with complex modulatory functions </li></ul><ul><li>In the peripheral nervous system, norepinephrine is the transmitter of the sympathetic nervous system </li></ul><ul><li>Norepinephrine can then be converted to epinephrine </li></ul>
  21. 21. Removal of Catecholamines <ul><li>All three catecholamines are removed by selective reuptake by the presynaptic axon terminals </li></ul><ul><li>They are either reused or degraded by monoamine oxidase (MAO) </li></ul><ul><li>Amphetamines and cocaine block the reuptake of catecholamines, thereby prolonging their synaptic action </li></ul>
  22. 22. Norepinephrine
  23. 23. Dopamine & Norepinephrine
  24. 24. Close Cousins?
  25. 25. Serotonin <ul><li>Derived from the amino acid, tryptophan </li></ul><ul><li>Belongs to a group of compounds called indoles </li></ul><ul><li>Serotonergic neurons are found in the brainstem </li></ul><ul><li>Involved in regulating attention & other complex functions </li></ul>
  26. 26. Serotonin Synthesis <ul><li>2 enzymes synthesize serotonin </li></ul><ul><li>Synthesis: </li></ul><ul><li>Tryptophan (from the diet via the blood stream) is converted to 5-HTP by tryptophan hydroxylase </li></ul><ul><li>5-HTP is converted to serotonin (5-HT) by 5-HTP decarboxylase </li></ul>
  27. 27. Serotonergic Neurons <ul><li>Use serotonin (5-HT) as a neurotransmitter </li></ul><ul><li>Because tryptophan comes from the diet, serotonergic neurons can be quickly affected by dietary deficiencies in tryptophan </li></ul><ul><li>Removal: </li></ul><ul><ul><li>Selective reuptake by the presynaptic axon terminals </li></ul></ul><ul><ul><li>Either reused or degraded by MAO </li></ul></ul>
  28. 28. Seratonin
  29. 29. Importance of Amine Transmitters <ul><li>These compounds (serotonin, dopamine, epinephrine & norepinephrine) play an important role in mental & neurological dysfunction: </li></ul><ul><li>Depression </li></ul><ul><ul><li>antidepressant drugs enhance neurotransmission at serotonergic and adrenergic synapses </li></ul></ul><ul><li>Schizophrenia </li></ul><ul><ul><li>involves dopaminergic neurotransmission </li></ul></ul><ul><li>Drug addiction </li></ul><ul><li>Parkinson's disease </li></ul><ul><ul><li>associated with decreased production of dopamine </li></ul></ul><ul><ul><li>treated with L-DOPA </li></ul></ul>
  30. 30. Neuropharmacology <ul><li>Many neurological diseases and mental disorders represent malfunctions of the synaptic transmission </li></ul><ul><li>These can often be treated by drugs which restore synaptic transmission. </li></ul><ul><li>Inhibitors or receptor antagonists : </li></ul><ul><ul><li>bind to postsynaptic receptor and block normal action of a neurotransmitter </li></ul></ul><ul><li>Receptor agonists : </li></ul><ul><ul><li>mimic the actions of normal neurotransmitters </li></ul></ul>
  31. 31. What Drugs?
  32. 32. Histamine <ul><li>Acts as a local hormone (autocoid) </li></ul><ul><li>Involved in control of blood vessels, inflammatory response, etc. </li></ul><ul><li>Also acts as a neurotransmitter in invertebrates </li></ul>
  33. 33. Amino Acid Transmitters <ul><li>Unlike acetylcholine & biogenic amines, these are universal parts of cells </li></ul><ul><li>Glycine & glutamate are common parts of proteins </li></ul><ul><li>GABA </li></ul><ul><ul><li>is synthesized from glutamate </li></ul></ul><ul><ul><li>is a major inhibitory transmitter at many sites in brain </li></ul></ul><ul><li>Common amino acids act as transmitters in some neurons, not in others </li></ul><ul><ul><li>shows that the presence of a substance doesn’t make it a transmitter </li></ul></ul>
  34. 34. ATP & Adenosine <ul><li>ATP & degradation products such adenosine can serve as neurotransmitters at some synapses </li></ul>
  35. 35. Neuroactive Peptides <ul><li>More than 50 pharmacologically active peptides are known </li></ul><ul><li>Serve important functions: </li></ul><ul><ul><li>Some modulate emotions </li></ul></ul><ul><ul><li>Some located in regions of brain involved in pain and pleasure perception </li></ul></ul><ul><ul><li>Substance P </li></ul></ul><ul><ul><li>Endorphins/Enkephalins </li></ul></ul><ul><li>Others respond to stress </li></ul><ul><ul><li>Endorphins </li></ul></ul><ul><li>  </li></ul>
  36. 36. Families of Neuroactive Peptides <ul><li>Grouped into families: </li></ul><ul><ul><li>Opioid </li></ul></ul><ul><ul><li>Neurohypophyseal </li></ul></ul><ul><ul><li>Tachykinins </li></ul></ul><ul><ul><li>Secretins </li></ul></ul><ul><ul><li>Insulins </li></ul></ul><ul><ul><li>Somatostatins </li></ul></ul><ul><ul><li>Gastrins </li></ul></ul>
  37. 37. Transmitter Binding <ul><li>The same transmitter can bind different receptors, resulting in different actions. </li></ul><ul><li>Receptor binding determines the effect, not the transmitter itself. </li></ul><ul><li>In related animals, each type of transmitter binds to a family of receptors and is associated with certain functions </li></ul><ul><li>Example: acetylcholine = synaptic excitation at neuromuscular junctions in vertebrates </li></ul>
  38. 38. Transmitter Binding
  39. 39. Dale's Principle <ul><li>Dale postulated that each neuron releases one and only one neurotransmitter </li></ul><ul><li>This is generally true for amino acid and amine neurotransmitters </li></ul><ul><ul><li>however, a peptide often accompanies the amino acid or amine </li></ul></ul><ul><li>Sometimes many peptides are released from one neuron </li></ul>
  40. 40. Which Neurotransmitter? <ul><li>How is the neurotransmitter traffic controlled? </li></ul><ul><ul><li>Slow or intermittent activity causes the release of the amino acid or amine transmitter </li></ul></ul><ul><ul><li>Only sustained high levels of activity, or many long bursts cause the peptides to be released </li></ul></ul>

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