the synapse sir charles sherrington 1897
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THE SYNAPSE Sir Charles Sherrington (1897)

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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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chemical transmission
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
silly idea
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”
what happens
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
and then
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
the synapse unidirectional
The Synapse: unidirectional

20 x 10-9m

Axodendritic: most common

types of synaptic connections
Types of synaptic connections

Presynaptic Inhibition or Facilitation

slide10

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

dale s law one neuron one neurotransmitter but
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
synthesis of neurotransmitters
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
control of transmitter release
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
autoreceptors
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
heteroreceptors
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
production of a sharply timed signal
Production of a “sharply timed” signal
  • Enzymic breakdown
  • Re-uptake by presynaptic terminal
  • Uptake by nearby glial cells
slide18

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

two receptor superfamilies
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
class 1 ionotropic receptor
Class 1 ionotropic receptor

Rapid response <1ms

eg nAChR,GABAA Receptor,

Glutamate NMDA (N-methyl-D-aspartate) receptor (Ca2+)

class 2 metabotropic receptors
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
class 2 gpcr
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

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