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 trans-

mission - 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

p o st-syna p ticp re -syna p tic

Na +

gap junction

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

Stimulated EPSP overlaid traces

EPSP - excitatory post-synaptic potential

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

Vesicle cycling? fusion hypothesis kiss & run

clathrin coating

fusion

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

temporal summation

spatial summation

Reversal of IPSPs

Inhibitory post-synaptic 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

e xc ita tio n

Dia g ra m o f syna p tic re sp o nse

Dia g ra m o f syna p tic la yo ut

p o stsyna p ticinh ib itio n p re syn a p tic

inh ib itio n

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