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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THE SYNAPSE Sir Charles Sherrington (1897)

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The synapse sir charles sherrington 1897

THE SYNAPSESir Charles Sherrington (1897)

presynaptic

postsynaptic


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”


The synapse sir charles sherrington 18971

THE SYNAPSESir Charles Sherrington (1897)

presynaptic

postsynaptic


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


Summation of ipsp epsp

Summation of IPSP/EPSP


The synapse sir charles sherrington 1897

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


Many others

Many others…………..


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


The synapse sir charles sherrington 1897

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


Class 2 receptor 2nd messenger systems

Class 2 receptor: 2nd messenger systems


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