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THE SYNAPSE Sir Charles Sherrington (1897)

THE SYNAPSE Sir Charles Sherrington (1897). presynaptic. postsynaptic. Chemical Transmission. In 1921 Otto Loewi had a dream…….. Perfused frog heart, and stimulated vagus nerve Heartbeat slowed (parasympathetic inhibition) Perfusate transferred to an unstimulated heart

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THE SYNAPSE Sir Charles Sherrington (1897)

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  1. THE SYNAPSESir Charles Sherrington (1897) presynaptic postsynaptic

  2. Chemical Transmission • In 1921 Otto Loewi had a dream…….. • Perfused frog heart, and stimulated vagus nerve • Heartbeat slowed (parasympathetic inhibition) • Perfusate transferred to an unstimulated heart • It too beat more slowly • Inferred inhibitory substance (“Vagusstoff”) • Identified as Acetyl Choline

  3. Silly Idea…….. • “It was an unlikely assumption that the vagus should secrete an inhibitory substance” • “Even more unlikely that a substance supposed to be effective at close range….be secreted in large amounts that it would spill over, and after being diluted……still be able to inhibit another heart”

  4. THE SYNAPSESir Charles Sherrington (1897) presynaptic postsynaptic

  5. What happens….. • Wave of depolarisation reaches axon terminal • Voltage operated Ca2+ channels open • Calcium influx cause transmitter-filled vesicles to fuse with presynaptic membrane • Neurotransmitter is released into synaptic cleft via exocytosis • Neurotransmitter bind to receptors in postsynaptic membrane • Opening of postsynaptic ion channels

  6. And then…….. • Post-synaptic current causes excitatory or inhibitory postsynaptic potential that changes the excitability of the postsynaptic cell • Vesicle membrane retrieved from plasma membrane • Neurotransmitters re-synthesised and stored in vesicles

  7. The Synapse: unidirectional 20 x 10-9m Axodendritic: most common

  8. Types of synaptic connections Presynaptic Inhibition or Facilitation

  9. Summation of IPSP/EPSP

  10. Stimulate same opioid receptors as heroin and other opiate drugs of abuse (3 –40 AAs) (Role in anxiety) Similar effect to cannabis (9- (4.H2O)cannabinol

  11. Many others…………..

  12. Dale’s Law: one neuron, one neurotransmitterbut…… • Neuropeptides and amines can co-exist • Neuropeptides modulate release of amine • eg neurotensin inhibits release of dopamine from some forebrain neurones

  13. Synthesis of neurotransmitters • Most neurotransmitters synthesised at “point of use” • Biosynthetic enzymes in terminal bouton • eg choline-O-acetyl transferase  Ach • eg tyrosine-3-hydroxylase, dopa decarboxylase, dopamine--oxidase  noradrenaline • Neuropeptides synthesised in soma and transported to synaptic bouton

  14. Control of Transmitter Release • Rate of Firing • “Probability of Release” • Variable depending on CNS location • P from 0.1 to 0.9 • Presence of autoreceptors on axon terminals or cell bodies • Presence of heteroreceptors at axo-axonal terminals

  15. Autoreceptors • Terminal • Inhibit transmitter release • Important in rapid firing • Somato-dendritic • Found on cell body or dendrites • Slow rate of firing • Fewer action potentials reach axon terminal

  16. Heteroreceptors • Receptors for a different transmitter at axo-axonal terminals • eg 2 receptor on presynaptic membrane of a noradrenaline-containing neurone is an autoreceptor • If 2 receptor on5-HT neuron, then it is a heteroreceptor • Often inhibit NT release by reducing opening of calcium channels

  17. Production of a “sharply timed” signal • Enzymic breakdown • Re-uptake by presynaptic terminal • Uptake by nearby glial cells

  18. MOA; catechol-O-methyltransferase (COMT) GABA inactivated by reuptake into presynaptic neuron and into astrocytes DAT; 5-HTT (or SERT), NAT, NET eg acetylcholin- esterase

  19. Two Receptor Superfamilies • Class 1 • Ligand-gated ion channel (LGICR) • = ionotropic • G-protein coupled (GPCR) • = metabotropic • Both are proteins with 3 domains • 1) extracellular • 2) lipophilic membrane-spanning • 3) cytoplasmic

  20. Class 1 ionotropic receptor Rapid response <1ms eg nAChR,GABAA Receptor, Glutamate NMDA (N-methyl-D-aspartate) receptor (Ca2+)

  21. Class 2, metabotropic receptors • Less immediate, longer lasting • NT binds to receptor • Conformational change activates G (= guanine nucleotide) protein • Open ion channels • Activates second messenger system

  22. Class 2, GPCR • G protein opens ion channel • or • G protein activates effector enzymes • 2nd messengers • Phosphorylate key proteins (kinases) • Cellular effects effector enzyme 2nd messenger system

  23. Class 2 receptor: 2nd messenger systems

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