Transcript Synaptic transmission

Synaptic
transmission
Module 725 Lecture 2
Aim
 Why do we need synapses?
 To know about chemical synapses
 diversity
 flexibility
 mechanisms
Overview
 Neurotransmitters
 Synaptic structure
 Transmitter release
 Transmitter breakdown/uptake
 Ionotropic receptors
Neurotransmitters
 Acetylcholine
 amino-acids
 glutamate
 GABA
 peptides
 FMRFamide
 NO (see next week)
Synaptic structure
 Neuromuscular junction
 CNS synapses
 Common features
 transmitter
stored
in vesicles
 receptors on postsynaptic membrane
 cell-cell signalling
to organise synapse
Neuromuscular junction
CNS synapses
Overview of physiology
 Simulation at
http://lessons.harveyproject.org/developm
ent/nervous_system/cell_neuro/synapses/
release.html
Transmitter release
 calcium-dependent
 vesicle cycling - or kiss and run
Calcium domains
 squid giant
synapse
 use n-aequorin-J
as Ca indicator
Calcium-dependency
 Calcium entry very near vesicle!
 micro or even nano-domains
 synaptotagmin as Ca sensor ?
Vesicle cycling
 Conventional view
 need recycling because no evidence of
increase in membrane area
 e.g.
capacitance
measurements
Vesicle proteins
 synaptobrevin & SNAP-25 anchor vesicle
membrane to plasma
membrane
 syntaxin helps in
conformational change
 synaptotagmin
as Ca sensor
Synaptotagmin
 calcium sensor
 arginine
in C2A and C2B domains
Exocytosis
 free energy
barriers need to
be overcome
during fusion
Endocytosis
 Clathrin coats “empty”
vesicles
Movie from
http://www.hms.harvard.edu/news/clathrin/
Kiss and run
testing… testing...
 capacitance measurements- measures
surface area
 GFP-derivative called synaptophlorin reports
pH (vesicles very acid)
 FM dye which fluoresces only in membrane
Summary so far
 transmitter put into vesicles
 vesicle release is Ca-dependent
 major protein players include
 synaptotagmin
 SNARE
 clathrin
Breakdown or uptake?
 esterase (ACh, peptides)
 transport - mostly into glia (amino acids)
Re-uptake
 12 membrane spanning regions
 co-transport using Na gradient
Uptake inhibitors
 major drugs
 cocaine
- block serotonin & dopamine
reuptake
 Prozac - selective serotonin reuptake
inhibitors
serotonin
cocaine
prozac
Summary so far
 transmitter put into vesicles
 vesicle release is Ca-dependent
 transmitter recycled
 after
breakdown
 direct pump for reuptake
Ionotropic receptors
 Ionotropic receptors have an integral
channel which opens when receptor binds
 Metabotropic receptors activate a second
messenger internally
 Important ionotropic receptors include
 nicotinic
ACH receptor
 glutamate (NMDA, AMPA, Kainate)
 GABA
Nicotinic ACh receptor
 2 a, one each of b, g , d
 ACh binds to a - need 2 ACh to open channel
Nicotinic ACh receptor
 highly conserved residues binding ACh
Glutamate receptor
 2 a, one each of b, g , d
 glu binds to a - need 2 glu to open channel
 NMDA receptors also
need glycine
Multiple glu receptors
 Named after agonists
NMDA receptors (I)
 blocked by Mg, except at depolarised
voltages
 need glycine as cofactor
squirt a-a and
see cell current
NMDA receptors (II)
 may provide
slow component to synapse
stimulate presynaptic
neuron and
see cell current
AMPA & Kainate receptors
 May both be used at same synapse
 stimulate presynaptic cell and record voltage
 APV
blocks NMDA, GYKI blocks AMPA
LY293558 blocks kainate
GABAA receptor
GABAA - drug action
 Benzodiazepines e.g.
Valium (=diazepam)

hypnotic, anxiolytic,
anticonvulsant,
myorelaxant and
amnesic
 Barbiturates e.g.
pentobarbital

sedative action
GABAA - diazepam
control
 longer openings in bursts
DZ
Summary
 transmitter put into vesicles
 vesicle release is Ca-dependent
 transmitter recycled
 after
breakdown
 direct pump for reuptake
 ionotropic receptors
 great diversity
 homologous subunits
 Synaptic transmission major drug target