Transcript Mechanism of synaptic actions and neuromodulation

Lecture 2 Synapses
Neuron-cell communication
http://biolpc22.york.ac.uk/632/nervelectures.html
Aim
 to know:
mechanism of synaptic action
 drugs which interfere with synaptic action
 diseases of synapses

Reading Matter
 Book

Nicholls DG (1994) Proteins Transmitters and
Synapses. Blackwell
 Papers:
Jessell TM, Kandel ER (1993) Synaptic transmission - a bidirectional and self-modifiable
form of cell-cell communication Cell 72S 1-30
 Whittaker, V. (1990) The contribution of drugs
and toxins to understanding of cholinergic
function Trends Pharm Science 11: 8-13 (in the
photocopy collection)

Revision
 Neurons have channels
voltage gated
 ligand gated

 Resting and action potentials depend on
voltage gated channels
 Connections between neurons usually called
synapses
Electrical connections
 Membrane resistance too
high for direct current
flow from cell to cell
Na
+
gap junction
pre-synaptic
post-synaptic
Chemical connections
 release chemical transmitter
 respond with receptors
 advantages
effective
 excite or inhibit
 variable gain

 disadvantages

slower than electrical [??]
Examples of synaptic
connections
 Examples from snail neurons

Excitation

Inhibition
Schematic diagram
 neuromuscular junction
Freeze fracture
 resting
 stimulated
Quantal release
 Miniature EPSP

time traces
EPSP - excitatory post-synaptic potential
 Stimulated EPSP

overlaid traces
Ca++ needed for
release
 Ca++ dye in
presynaptic
neuron
 [Ca] rises at end
of action
potential
Ca++ block stops
synapse
 presynaptic Vm
(voltage clamp)
 presynaptic I Ca++
 postsynaptic Vm
Ca++ block stops
synapse
 presynaptic
EGTA blocks
transmission
control
EGTA
Vesicle fusion cycling
fusion
 Vesicle cycling?


fusion hypothesis
kiss & run
 clathrin coating
kiss & run
Synaptic Toxins
 tetanus & botulinum
toxins

blocks transmitter
release


interacts with
(vesicle/membrane proteins)
produced by Clostridium bacteria
ACh cycling
ACh pumped into vesicle
ACh esterase
Summary so far
 transmitter is stored in vesicles
 vesicles released calcium influx nearby
 calcium influx triggered by depolarisation
from action potential
Pharmacology of
receptors
 many kinds of receptors




ACh
glutamate, glycine
serotonin, dopamine
peptides, FMRFamide
 separate pharmacologically

each receptor binds its own
unique profile of drugs
Pharmacology of
receptors
 Nicotinic ACh receptor


agonist - nicotine,
succinylcholine
antagonist - curare,
bungarotoxin
 Muscarinic ACh
receptor


agonist - muscarine
antagonist - atropine
Ionotropic &
Metabotropic
 Ionotropic


receptor binding opens
hole
ions flow through
 metabotropic




receptor binding activates
G-protein
requires second
messenger
7 transmembrane format
phosphorylates another
protein [channel]
Second messengers
 make synapses slow
 cAMP
 IP3/DAG/PKC
 arachidonic acid
= = norepinephrine
How does 5-HT act?
 apply 5-HT to cell
 patch elsewhere
Effect of 5-HT
 5-HT could




block a channel
reduce chance of
opening
increase chance of
closing
reduce current
5-HT = = serotonin
Effect of 5-HT
 5-HT closes K+ channels


channel size the same
reduced chance of opening
Summary so far
 transmitter is stored in vesicles
 vesicles released calcium influx nearby
 calcium influx triggered by depolarisation
from action potential
 multiple kinds of receptor
ionotropic / metabotropic
 different transmitters

Excitation and
inhibition
spatial summation
temporal summation
Reversal of IPSPs
 Inhibitory postsynaptic potentials
reverse at -70 (K+)
or -50mV (Cl-)
Pre- & Post- synaptic
inhibition
 Post-synaptic inhibition
leads to summation of
excitatory and inhibitory
transmitter
 Pre-synaptic inhibition
occurs between two
axons

it prevents release of
transmitter
Diagram of synaptic layout
exc itation
postsynaptic
inhibition
presynaptic
inhibition
Diagram of synaptic response
Transmitters & disease
 myasthenia gravis

autoimmune response to ACh receptor
 Parkinson’s disease

loss of dopaminergic neurons
Confusing points to
watch out for
 Note the difference between



inhibition and antagonism
pre- and postsynaptic inhibition
conduction and conductance
Summary to end
 transmitter is stored in vesicles
 vesicles released calcium influx nearby
 calcium influx triggered by depolarisation
from action potential
 multiple kinds of receptor

ionotropic / metabotropic


fast/slow
different transmitters
 excitatory / inhibitory