neurotransmitters and pharmacology Flashcards
what does information transfer across a synapse require
a neurotransmitter and their interaction with postsynaptic receptors
summarise synaptic transmission in 4 steps
1) NT release from 1st cell
2) synaptic activation of 2nd cell
3) signal integration and signal conduction by 2nd cell
4) signal transmitted to effectors or subsequent neurones
4 features of synaptic transmission
rapid timescale
diversity of CNS function
plasticity
learning and memory
what is the structure of a neuron and how does it relate to synaptic transmission
dendrite (spines where info is received)
soma (body where info is integrated)
axon and synaptic terminals (where info is transferred rapidly by AP)
what is the soma
cell body
every neurone has one
what is the end of the axon called
synaptic terminal
what do dendrites have that increase SA for info receiving
proteins called spines
what does the cell body do
integrate info
what is AP
electrical transmission
chemical transmission occurs at the synaptic cleft
how big is the synaptic gap/cleft
20-100nm
STEPS for NT (3)
1) biosynthesis, packing and release of NT
2) NT released by exocytosis and receptor action on post synaptic neuron
3) inactivation of NT after activation on receptor
what are 3 types of NTs within the central nervous system
amino acids
amines
neuropeptides
examples of amino acid neutrotransmitters
gluatamate
GABA
glycine
examples of amine neurotransmitters
noradrenaline
dopamine
examples of neuropeptide neurotransmitters
opioid peptides
STEPS for activation of a CNS synpase
1) arrival of AP
2) spreads across nerve terminal
3) activates depolarisation of entire nerve terminal (rapid Na+ influx and K+ efflux) which activates VGCCs > Ca2+ enters and goes to nerve terminal > activates exocytosis of vesicle with NT
4) released into the cleft
5) rapidly diffuses across gap down gradient
6) binds to receptors on postsynaptic membrane > excitatory synapse as receptors allow influx of Na+ into postsynaptic cell > depolarisation of postsynaptic cell and generation of another AP > passes down axon
7) NT generated response > inactivate rapidly (reuptake of NT)
8) activation of Na+/K+ pump > extrudes Na+ that came in and replaces it with K+ (functions independently of reuptake system)
9) or enzyme degradation in cleft eg acetylcholinesterase to break down acetylcholine
where is acetylcholinesterase found
bound to basolateral membrane in synaptic cleft
what does neurotransmitter release need
an increase in intracellular Ca2+ as it is calcium dependent
requires rapid transduction
what is electromechanical transduction
links opening of calcium channel > influx > NT release into cleft
SUMMARY of NT release
membrane depolarisation Ca2+ channels open Ca2+ influx vesicles are primed vesicle fusion vesicle exocytosis NT release
where are synaptic vesicles filled with NT docked
into synaptic zone
what enables vesicle fusion and exocytosis on vesicles and presynaptic membranes
special proteins
eg SNARE proteins (vesicular proteins) mediating process of exocytotic release of NT
what are targets for neurotoxins
vesicular proteins
example of neurotoxin = alpha latrotoxin
black widow spider
stimulates NT release to depletion
binds to cholinergic terminal and causes release of ACh until depletion leading to muscular paralysis
example of neurotoxin = Zn2+ dependent endopeptidases
inhibit NT release eg tetanus toxin (inhibits GABA release and glycine release leading to spasms and paralysis)
example of neurotoxin = botulinum toxin
C botulinum - generating botulinum toxin > can cause arrest
causes flaccid paralysis
made of 2 chains
1st chain binds to cholinergic nerve terminal
2nd chain penetrates the cholinergic nerve terminal and interacts with vesicular proteins
cleaves peptide bonds of vesicular proteins
can no longer dock/fusion/release of NT - inactivated
what are the 2 main groups of receptors
ion channel linked receptors (FAST)
G protein coupled receptors (SLOW)
what are ion channel linked receptors and examples
receptors that produce fast response
mediate all fast excitatory and inhibitory transmission
glutamate binds to receptor > stimulation > opening allowing influx of Na+ into cell > AP
GABA (CNS)
neuromuscular junction - ACh at nicotinic receptors
what are G protein coupled receptors
slow response
effectors may be :
- enzymes (adenyl cyclase, phospholipase C, cGMP-PDE)
- channels (eg Ca2+/K+)
examples
CNS and PNS : ACh at muscarinic receptors, dopamine (DA), noradrenaline (NA), serotonin (SHT) and neuropeptides (eg enkephalin)
how do G protein coupled receptors work (STEPS)
1) stimulated by agonist
2) bind to G protein in membrane
3) G protein couples to receptor
4) second messenger in cell
features of ion channel linked receptors
rapid activation
rapid info flow
multiple subunit combinations > distinct functional properties
what is the ion channel linked receptor for acetylcholine
nicotininc cholinergic receptors (nAChR)
what is the ion channel linked receptor for glutamate
GluR
what is the ion channel linked receptor for GABA
GABAR
what is the ion channel linked receptor for glycine
GlyR
how many subunits are there
around 5
GABA A receptors are..
inhibitory
glutamate receptors lead to..
depolarisation
STEPS for excitatory NT receptor
eg glutamate receptor
release of glutamate activating receptor on postsynaptic membrane
rapid influx of Na+ through channel (sometimes through receptor itself) down EC gradient
shoots into postsynaptic nerve
generates EXCITATORY POSTSYNAPTIC POTENTIAL (EPSP)
STEPS for inhibitory NT receptor
eg GABA
binds to GABAR
opens Cl- channel
Cl- enters
fall in membrane potential (hyperpolarisation)
leads to INHIBITORY POSTSYNAPTIC POTENTIAL
what exists between GABA and glutamate
a balance in the brain
what are the 2 types of glutamate receptors
AMPA receptors
NMDA receptors
describe AMPA receptors
majority of FAST excitatory synapses
rapid onset, offset and desensitisation
describe NMDA receptors
slow component of excitatory transmission
serve as coincidence detectors which underlie learning mechanisms
STEPS for excitatory glutamate synapse
1) glutamate synthesised from glucose via TCA cycle and transamination
2) glutamate reversibly binds postsynaptic receptors (linked to ion channels)
3) rapid uptake of glutamate by excitatory amino acid transporters (EAATs) excitatory AA transporters
4) glutamate enzymatically modified by glutamine synthetase to glutamine in glial cells
what receptors are found in the hippocampus
NMDA receptors
what are seizures
abnormal cell firing > seizures associated with excess glutamate in synapse
glutamate returns to normal levels > increase in glutamine levels (metabolised glutamate)
what is epilepsy
characterised by recurrent seizures due to abnormal neuronal excitability
disease can be disabling
25-30% refractory to treatment
new gen of drugs targeting GABA synapse
STEPS for inhibitory GABA synapse
1) GABA synthesised by decarboxylation of glutamate by glutamic acid decarboxylase (GAD)
2) GABA reversibly binds postsynaptic receptors (linked to ion channels)
3) rapid uptake of GABA by GABA transporters (GATs)
GABA enzymatically modified by GABA transaminase (GABA-T) to succinic semialdehyde (glial cells and GABA nerve terminals)
what does GABA do to action potentials
reduce AP frequency
harder to induce AP
structure of GABA receptor
pentameric organisation of GABA receptor > pharmacologically important binding domains
what are some drugs facilitating GABA transmission
antiepileptic anxiolytic - reduce anxiety sedative muscle relaxant enhance GABA inhibitory action
