synapses and neurotransmitters Flashcards
synapse
a specialised gap between 2 apposing cell membranes across which signals can pass
otto loewin discovered synapse
2 isolated frog hearts donor and recipient ensured vagus nerve was still attached at released from VN (parasympathetic nervous system) 1. stimulated vagus nerve of donor heart 2.heart rate slowed 3. transferred sulotion (vagusstoff-german) from donor to recipient (now known as Ach) 4. heart rate slowed in recipient heart
common feature of chemical synapses
presynaptic cell (usually axon terminal) mitochondria- help clear calcium from presynaptic terminals
secretorry granules- contain peptide neurotransmitters
synaptic vesicles contain amine?
both released at active zone (membrane differentiation)
post synaptic membrane (usually dendrite)
receptors
synaptic cleft (20-50 nm wide)
contains a matrix of fibrous extracellular protein
types of synapses
- neuron to non neuronal
most common= motor neurone to skeletal muscle, the neuromuscular junction
autonomic neurons to glands, smooth muscle, heart (otto leowie)
2. neuron to neuron within CNS (and between pre and post ganglionic neurons) v. varied different neurotransmitters different sizes and morphologies
why synapses
excitatory =more positive
inhibitory= more negative
convergence of input
one cell influenced by many others
convergence of output
one cell influences many others
neuromuscular junction
fast and reliable synapse
motor neurone action potentials always causes muscle cell action potentials
uses Ach
one of the largest synapses in the body
specialisations of the neuromuscular junction
presynaptic: large number of active zones
post synaptic (motor end plate) contains junctional folds, densely filled with neurotransmitter receptors (more of them due to larger surface areas)
at can bounce around in folds before getting degraded
precise alignment of active zones and junctional folds
CNS synpases
around 86 billion neutrons in the human brain so TOO MANY SYNAPSES TO COUNT
arrangement:
a) axodendritic (axon to dendrite)
b) axosomatic (axon to soma)
c) axaonic (axon to axon)
d) dendodendritic (dendrite to dendrite) could be inhibitory ? presynaptic
end bulb of held- auditory system
reliable type of synapse
hearing = very important e.g. danger
plasticity
synapses can grow /shrink /change in size
larger synapses usually have more active zones
variability of CNS synapses
Asymmetrical membrane differentiation= excitatory
symmetrical membrane differentiation = inhibitory
USUALLY
brief cascade of events of depolarisation
more postivie
voltage gated ca2+ open (around -40mv- -10mv)
rise in ca2+ triggers fusion of vesicles to pre synaptic membrane
diffusion of ca2+
release of neurotransmitters
diffusion across cleft
not every nt will come into contact with a receptor
the smaller the gap the more likely they are to bind
types of NT
amino acids (synaptic vesicles)
amines( ‘’)
peptides (dense core secretory vesicles)
amino acids
Glu, GABA, Gly
amines
ACh, NE
peptides
Arg, Pro, Lys, Gln,
synaptic vesciles
amino ancid and amine NT
40-50 nm diameter
synthesies in soma
filled at presynatpci terminal requires ATP to load neurotranmitter into vesicles
dense core secretory vesicles
peptide NT 100-200 nm diameter senthesied in ER often as precursors bud from the golgi apparatus in soma transported along microtubules
Peptide neurotransmitters are formed in the rough ER. Sometimes formed as longer precursor proteins that are cleaved and processed through the Golgi apparatus. Vesicles are transported by fast axonal transport using the microtubule system.
where are vesicles made
All vesicles are made in the cell body but synaptic vesicles are transported empty.
abundant nt
- The Amino acid neurotransmitters glutamate and glycine are abundant in all cells as they are used as the building blocks of proteins.
GABA and amines
GABA and the amines are made only in the neurons that release them. The neurons need special enzymes that enable them to synthesise the neurotransmitters from various metabolic precursors. These enzymes are found in the presynaptic terminals to allow rapid and local neurotransmitter synthesis. Specialised transporters take the neurotransmitters up into synaptic vesicles.
docking of vesicles
some vesicles are already docked at active zones within the presynaptic neuronal membrane
vesicles are held in place with snare proteins ready to be released
arrival of action potential
opens voltage gated ca2+ channels
depolarisation!
ca2+ moves into the presynaptic terminal as Eca2+ is about 123 mV
triggers vescles fusion and release (exocytosis)
SNARE proteins
some present of pre s membane and some present on vesicles
synaptotagmin binds calcium and changes the configuration and moves the vesicle closer to the pre s membrane
botulinum (BOTOX) from the black widow spider is an enzyme that selectively destroys some SNAREs and block the neurotransmission
synapses between the nerves and the muscles are disrupted by the toxin
diffusion
the synaptic cleft has a very small volume so nt conc can rise to the mM (millimolar) range
NT action
specific receptors are embedded in the post s density
some nt will bind to the receptors
2 types of nt receptors
ligand-gated ion channels (ionotropic)
G protein coupled receptors (metabotropic)
Fate of NT
nt must be cleared rapidly from the cleft
3 ways:
- simple diffusion out the cleft to the side (either before or after activation at receptor)
- reuptake into pre s membrane or glia by specific transporter for recycling (sometimes)
- enzymatic destruction within the cleft e.g. ach enzyme (acetylcholinesterase)
what happens to the vesicle
when it fuses it adds to the terminal membrane and becomes larger
(can measure this - compasitence measurement)
then has to recognised by molecules to be endocytose back into membrane
vesicles can be recycled and filled with new nt
quantal release
each synaptic vesicles contains about 35-50 nM and can cause mini response at the post synaptic cell
the effect of one vesicles being release is the quantal size
quantal content is the number of quanta (or vesicles) released
receptor dependent action
ligand gated ion channel permeable to Na+ e.g. at skeletal muscles contraction
immediate effect
G protein coupled receptor
slower and more complicated
activating K+ channel (parasympathetic) e.g. heart slows down
transmitter release at a fast excitatory chemical synapse generate an excitatory post synaptic potential (EPSP) e.g. nicotinic ACh receptors
EPSP propogate to soma
cause membrane to reach threshold
enough EPSP at one time you get a summation
IPSP
transmitter release at a fast inhibitory chemical synapse generate an inhibitory post synaptic potential
e.g. GABA a receptor (ionitropic chlride channel)
opening of pore and chloride moves into cell
cell more negative
hyperpolarised
takes potential further away from the threshold for AP firing
G protein coupled receptors
metabotropic
transmission is slower
and more complex than transmission via ligand gated ion channels
signal amplification occurs
1 NT and 1 receptor can activate multiple g proteins
multiple channels may be affected
criteria for NT
present in pre s terminals
released in response to stimulation
able to interact with post s receptors
rapidly removed from the synapse (timing of signal lost otherwise)
NT needs mechanisms
for syntheis and storage
for release
for transmitter action (i.e. receptors) and removal
types of transmitters
achetlcholine
amino acids (GABA, Glycine, Glutamic acid, asperatic acid)
biogenic amines (catecholamines: epinephrine, norepinephrine, dopamine// serotonin, histamine)
neuropeptides: enkephalin substance P cholecystokinin B- endorphin
the amino acids and amine nts are
small molecules
stored and released from synaptic vesicles
capable of biding to and activating both
- ligand gated channel receptors
- g protein coupled receptors
short term and long term signalling
the peptide nts are
large stored in secretory grnaules made in soma only activate G protein coupled receptors (don't activate ligand gated ion channels) slower/modulatory nts
Dale’s principle
famous 1940s scientist
‘a neuron has only one nt’
classifed neutrons into mutually exclusive groups by the nt they released
BUT
many peptide containing neurones ave both peptide and aa or amine MT as well (or co transmitters e.g. ATP)
soe neurons also possess two types of aa NT e.g. GABA and glycine (co released)
therefore Dale’s principle is violated in these cases
glutamate
most common excitatory nt in CNS
aa therefore found in all neurons (aa used to build proteins)
(because glutamate is everywhere, to know whether a neutron is glutamenergic, the molecule that loads it into vesicle is the marker)
3 glutamate receptor subtypes based on the drugs which act as selective agonists:
AMPA, NMDA and Kainate
action is terminated by selective uptake into presynaptic terminals and glia
glutamate at receptor lelvel
AMPA receptors mediate fast excitatory transmission
permeable to cations
let more sodium in than potassium moves out
glutamate binding to AMPA receptors triggers NA and K currents resulting in an EPSP
NMDA receptors
permeable to calcium and sodium
often co exist with AMPA receptors
NMDA receptors have a voltage dependent MG2+ block
so NMDA receptors need to be indirectly activated by another transmitter
NMDA recpetors are percale to ca2+ as well as na and k
therefore their activation can have more widespread, lasting changes in postsynaptic cell
really important for plastic memory strengthening synapses
GABA
major inhibitory
CNS
not an aa used to build proteins
transformed from glutamate by GAD (glutamic acid decarboxylase)
GAD used to know whether a neurone is GABAergic
action is terminated by selective uptake into presynaptic terminals and glia
action of GABA
produces IPSPs via GABA gated chloride channels (hyperpolarisation)
found throughout the CNS especially in cortex and striatum
the right amount of inhibition via GABA is critical:
too much=coma / loss of consciousness
too little = seizures
why is GABA excitatory in development but inhibitory in adults ??!!
chloride conc can be changed - in cells in development we have different cl transporters which make sure more chloride inside cell at rest than in adult
because more chloride is increased inside cell -
negative outside
more postive =depolarised
presynaptic inhibition GABA
one neutron suppresses the action of another
or auto inhibition - gabaergic neutron can inhibit itself
keeps a specific timing of a signal
disinhibition
inhibiting inhibition
modulation of GABAa receptors
1) ethanol has behavioural effects, addictive (because exaggeration gaba a = more inhibition)
2) benzodiazapine e.g. diazepam used to treat anxiety (enhances gabaergic response, increases inhibition)
3) barbiturates are sedatives and anti-convulsants
4) neurosteroids are metabolites of steroid hormones e.g. progesterone which can effect gaba receptors
when females have mood changes over mentrual cycle
PMT is real!
GABA a receptors
PET scan from patient with panic attack
can label with benzodiazepine e.g. diazepam
shows loss of GABAa receptors
Opioids derived from
opiod poppy
e.g. heroine and morphine
opiods can be natural and synthetic
e,g, endorphins- nautrally occcuring small proteins or peptides including endorphin, enkephalin and dynorphin
or drugs (synthetic)
how and when were opiod receptors discovered
1973 using radioactively labelled opiate compounds
when were endorphins discovered?
1975
because opioids are peptides where are they synthesised
formed in the rough ER and packaged into secretory granules by Golgi
distribution of opioid receptors
widely distributed in CNS but concentrated in nociceptive areas
have at least 3 main types Include mu (µ), kappa, sigma
spinal opiate receptors
block pain signal (analgesia)
periaqueductal grey
regulates sensation of pain
amygdala
regulates emotional compenent
frontal cortex
cognitive aspects
brain stem (medulla)
depress respiration and cough reflex (may induce vomiting) if overstimulate receptors here then get v low breathing rate
opiate receptors act as modulators, decreasing the excitability of the cell, how?
can prevent voltage gated calcium channels opening or increase opening of the potassium channels, both hyperpolarise the cell
receprors coupled to inhibitory G proteins
therapeutic uses of opiates
Analgesia: reduces perception of and emotional response to pain
intestinal disorders:
reduces diarrhoea, decreases dehydration
Antitussive: cough supressant (codeine)
problems with therapeutic use of opiates
serious side effects:
respiratory depression
sedation
constipation
tolerance developed- rescued cancel effect
dependence developed - withdrawal symptoms
releive dull visceral pain better than sharp pain
catecholamines
dopmamine and noradrenaline
synthesis of Ach
Acetyl CoA + Choline—–(choline actyltransferase ChAT)—-> Ach +CoA
degradation of Ach
Ach—–actylcholinesterase—-> acetic acid + Choline
ChAT
choline acetyltransferase
a good marker for cholinergic neurones
Acetyl CoA
produced by cellular res in mito
chemicals that prevent release of Ach
botulinum toxin (produced by bacteria)
black wider spider venom (latrotoxin) first increases ACh release at NMJ then eliminates it. Seems to work by allowing a big calcium influx.
AChE inhibitotrs
nerve gas
insecticides
Alzheimers treatments
Chemicals that block Ach Receptors
nicotinic
- curare
- alpha bungarotoxin
Alpha bungarotoxin from snake venom binds to nAChRs and takes days to unbind.
Muscarinic
-atropine
ACh 2 cholinergic complexes
1) basal forebrain complex
amongst first neurones to die in alzehiers disease
regulate brain excitability during sleep/wake cycles + arousal
possible role in learning and memory
2)Pontomesencephalotegmental complex (brainstem)
synthesis of catecholamines
1) tyrosine= amino acid
–tyrosine hydroxylase->
2) L-Dihydroxyphenylalanine (dopa)
—dopa decarboxylase—>
3) Dopamine
- Dopamine B-hydroxylse–>
4) Noradenaline
—phentolamine N-methlyltransferase(PNMT)–>
5) Adrenaline
Tyrosine hydroxylase
present in all catecholaminergic neurons
rate limiting factor
Dopamine β-hydroxylase
found in synaptic vesicles
PNMT
found in the cytosol
MAO-A (monoamine oxidase)
on outer mito membrane
metabolises noradrenaline and 5HT mainly
MAO-B
mainly metabolises dopamine
catechol-O- methyltransferease (COMT)-
degrades catecholamines in cytoplasm
nigrostriatal pathway
Neurons found in the substantia nigra of the midbrain
Axons project to the striatum
Pathway facilitates the initiation of voluntary movements
Degeneration of this pathway leads to Parkinson’s disease
Characterised by motor dysfunction e.g. tremor, rigidity
treating parkinsons with addition of L dopa
removes the rate limiting step of tyrosine hydroxylase, so increases dopamine levels
MAO-B inhibitors
reduce the breakdown of dopamine, increasing levels of it
mesocorticolimbic pathway
Neurons found in the ventral tegmental area of the midbrain
Axons project to the frontal cortex and limbic system
Assigned many functions
Involved in a ‘reward’ system i.e. pleasure
We are motivated to perform behaviours that stimulate dopamine release
Behaviours associated with the delivery of drugs which result in dopamine release are reinforced = addiction
noradrenergic system
arises form locus coeruleus
around 25,000 neurones
innervates nearly all of the brain
1 neutron can make 250,000 synapses
involved in regulating attention, aroudal, sleep-wake cycles, learning and memory, anxiety and pain, mood
most strongly activated by new unexpected non painful sensory stimuli
serotonergic system
arises from Raphe nuceli
each nucleus projects to a different area
similar sighs innervation of brain to noradrenergic system
modualted pain-ralted sensory signals, sleep/wake cycles, mood and emotions
most strongly activated during wakefulness
example caudal icily innervate spinal cord
5-HT life cycle
1) tryptophan: (from diet)
—tryptophan hydroxylase->
2) 5-Hydroxytrytophan
— 5HTP decarboxylase–>
3) 5-Hydroxytryptamine (serotonin, 5-HT)
tryptohan in 5HT life cycle
starting molecule
Obtained from our diet e.g. grains, meat, dairy, chocolate
Moves from gut to blood to extracellular fluid
Rate limiting factor in synthesis
treatment of affective disorders
tricyclic compounds- block uptake of 5HT and noradrenaline
- SSRIs selectively prevent 5HT uptake
e. g. prozac (fluxetine)
MAO-A inhibitors - reduce enzymatix degradation of 5HT and noradrenaline
the cheese effect
tyramine is an amine found in high quantities in cheese
it has a sympathomimetic effect by increasing noradrenaline release
MAO normal breaks down tyramine
MAO-A inhibitors leads to a hypertensive crisis
ATP
often packed into vesicles as a co-transmiter
binds to purinergic receptors
P2X= ligand gated ion channels
P2Y- g protein coupled receptors
Endocannabinoids
endogenous forms of cannabis
small lipid molecules that do not require synaptic vesicles
binds to cannabinoid receptors that are G protein coupled
Nitric oxide
Gasotransmitter that is small and membrane permeable
rapidly broken down
catecholamines
dopamine, noradrenaline and adrenaline
and are produced in a a series of enzymatic conversions
