L1 Bio

• Neurotransmitters


  Chemical messengers that transmit messages over the synapse
• Examples of neurotransmitters


  • Serotonin
  • Dopamine
  • Acetylcholine
  • Norepinephrine
  • Gamma amino butyric acid (GABA)
  • Glutamate
• Criteria for identifying neurotransmitters


  • Synthesized and stored in high concentrations in nerve terminals where it is released
  • Released upon stimulation of the nerve terminal, release is calcium dependent
  • Mimics action of presynaptic stimulation when postsynaptically applied experimentally
  • Antagonists of the synaptic response block its actions
  • A mechanism to inactivate the transmitter and therefore to terminate its action should exist

  
• Classification of neurotransmitters


  • Neurotransmitters of low molecular weight
  • Neuropeptides (chains of 3-40 amino acids)

  
• Norepinephrine and Acetyl choline are the principal neurotransmitters in the peripheral nervous system

  
• All Neurotransmitters except Neuropeptides are synthesized at the nerve ending where they are packaged into vesicles; Neuropeptides are synthesized in the cell body & transported down the axon

  
• A neuron may contain more than one neurotransmitter of low molecular weight, more than one neuropeptide, or both types of neurotransmitters

  
• Release of neurotransmitters


  1. Vesicles are attached to microtransmitters in resting state

  2. Action potential reaches presynaptic terminal, membrane depolarizes, voltage-gated calcium channels open and calcium ions move in

  3. Calcium ions help guide synaptic vesicles towards presynaptic membrane

  4. Vesicles fuse with presynaptic membrane

  5. Neurotransmitter is released

  6. Vesicles are recycled

  
• Neurotransmitter receptors


  Neurotransmitters need to bind to specific receptors on the postsynaptic neuron for effective transmission of impulses (action)
• Mechanisms for terminating the action of neurotransmitters


  • Reuptake into the presynaptic neuron for reuse
  • Metabolism by enzymes
  • Simple diffusion

  
• Reuptake into presynaptic neuron


  A major route for removal of catecholamines & amino acids, drugs can inhibit this process to exert an effect
• Metabolism by enzymes


  Acetylcholine is inactivated by acetylcholine esterase, epinephrine and norepinephine are metabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT), histamine is inactivated by histamine-methyltransferase
• Simple diffusion


  The major mechanism of removal of neuropeptides
• Catecholamines (norepinephrine, epinephrine & dopamine) are also known as Biogenic amines

  
• Synthesis of catecholamines


  1. Tyrosine is supplied in the diet or synthesized in the liver from phenylalanine

  2. Tyrosine is hydroxylated by tyrosine hydroxylase to form DOPA (cofactor BH4)

  3. DOPA is decarboxylated to form dopamine

  4. In norepinephrine-containing neurons, dopamine is hydroxylated by dopamine β-hydroxylase to form norepinephrine ( coenzyme ascorbic acid and copper)

  5. In the adrenal medulla, norepinephrine is methylated by N-methyltranseferase to form epinephrine (coenzyme SAM, B12, and folate)

  
• Short-term regulation of catecholamine synthesis

  Feedback inhibition: Tyrosine hydroxylase is inhibited by free cytosolic catecholamines

  Depolarization of nerve terminal activates tyrosine hydroxylase, resulting in an enzyme that binds BH4 more

  tightly, making it less sensitive to end-product inhibition.
• Long-term regulation of catecholamine synthesis


  Increased sympathetic neuronal activity increases mRNA for tyrosine hydroxylase and dopamine-hydroxylase, newly synthesized enzymes are transported to nerve terminals

  
• Storage and release of catecholamines


  Tyrosine to L-DOPA and L-DOPA to dopamine occurs in cytosol, dopamine is taken up into storage vesicles, final hydroxylation to norepinephrine occurs in vesicles, catecholamines exist in complex with ATP and chromogranins in vesicles, vesicles play dual role of storage and release

  
• Inactivation and degradation of catecholamines

  Reuptake into presynaptic terminal, degradation by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), MAO catalyzes oxidative deamination, COMT catalyzes methylation using SAM, degradation products include vanillylmandelic acid (VMA), metanephrine, and homovanillic acid (HVA)
• Vanillylmandelic acid (VMA) and metanephrine can be measured in urine as indices of adrenal medulla function, increased in pheochromocytoma
• Cerebrospinal homovanillic acid (HVA) is an indicator of dopamine degradation, decreased in Parkinson's disease
• MAO in the liver protects

  Ingestion of dietary biogenic amines like tyramine
• COMT acts on


  Extra-neural catecholamines & those that have diffused away from synapse