synapses and neurotransmitters Flashcards
electrical synapses
gap junctions to allow current to pass directly between neurons
cytoplasm becomes continuous through connexons (made of connexins)
large molecules e.g. proteins cannot get through
depolarisations and hyperpolarisations can be transmitted
very fast
chemical synapses
neurotransmitters are packed in vesicles
2 types of vesicle:
synaptic vesicle = small, small molecule neurotransmitters, transporter proteins fill the vesicles, recycled by endocytosis
dense-core secretory granules = large, peptide neurotransmitters, filled by ER and Golgi, used once and not reused
Ca2+ influx causes vesicles to be released into synapse
SNAREs
specialised proteins on vesicle membrane (v-SNAREs) and axon membrane (t-SNAREs)
synaptotagmin underwent confirmational change when Ca2+ binds to it
v and t SNAREs bind to each other and zip together to force vesicle and plasma membrane to fuse
e.g. Botox works by paralysing SNAREs so neurons cannot communicate
ionotropic vs metabotropic receptors
ionotropic = ligand-gated ion channels
directly depolarise or hyperpolarise postsynaptic cell
confirmational change causes channel to open when bound to
metabotropic = G-protein-coupled receptors
more complex effects - confirmational change triggered which activates G-protein and other downstream effects
electrical vs chemical synapses
electrical = both directions, direct signal, fast
chemical = one direction, signals can be transformed (amplified, inverted etc), slower
neuromuscular junction
acetylcholinergic synapses
presynaptic = many active zones
postsynaptic (motor end plate) = has junctional folds (densely filled with NTs) - precisely aligned with active zones
2 type of neurotransmitter
small molecules:
amino acids - GABA (modified amino acids)
amines - 5-HT, DA, acetylcholine, epinephrine
stored in synaptic vesicles
bind to ligand-gated ion channels or G-protein coupled receptors
large molecules:
proteins - smaller proteins
stored in secretory granules
only bind to G-protein coupled receptors
neurons usually only release one of these types
often peptide-releasing neurons also release a small molecule co-transmitter
glutamate - what is it
most common excitatory transmitter in CNS
amino acid - in all neurons
3 ionotropic glutamate receptor subtypes - based on drugs which act as selective agonists
- AMPA, NMDA, Kainate
action is terminated by selective uptake into presynaptic terminals
glutamate - AMPA receptors
mediate fast excitatory transmission
glutamate binding to AMPA triggers Na+ and K+ currents, resulting in EPSP (Na+ in, K+ out)
glutamate - NMDA receptor
often coexist with AMPA receptors
voltage dependent - blocked by Mg2+ - open when neuron is already depolarised
let in Ca2+ and Na+ and K+ out
downstream signalling) from Ca2+
coincidence detector - neuron is activated right after it was already activated - important for learning
glutamate - ionotropic vs metabotropic receptors
ionotropic:
4 subunits form a gated ion channel
e.g. AMPAR, NMDAR
fast (msec)
metabotropic:
G-protein coupled receptor, then downstream signalling cascade
e.g. mGluR1, mGluR2 etc
can allow glutamate to sometimes be inhibitory e.g. in retina
slow (sec-min)
GABA - synthesis, termination
amino acid (doesn’t synthesise proteins)
synthesised from glutamate by glutamic acid decarboxylase
terminate action by selective uptake into presynaptic terminals and glia
GABA - what is it, what it does
most common inhibitory transmitter in CNS
produces IPSPs (inhibitory postsynaptic potentials) via GABA-gated chloride channels (GABAa receptors) — WHEN membrane potential (Vm) is above chloride’s Nernst potential
channels allow Cl- into neuron from synapse
inhibition of GABA – right amount is critical
– too much = coma/loose consciousness
– too little - seizures
GABA - modulation of GABAa receptors
other chemical can bind to GABAa receptor and modulate response to GABA binding
these chemicals have no effects without GABA binding (allosteric):
- ethanol
- benzodiazepine (e.g. diazepam for anxiety)
- barbiturate - sedative and anti-convulsant
- neurosteroids - metabolites of steroid hormones e.g. progesterone
GABA - GABAb receptors
GPCRs (similar to mGluR (glutamate)
act differently in different cells
can open K+ channels, close Ca2+ channels, trigger secondary messengers e.g. cAMP
often presynaptic or autoinhibitory
glycine - what is it
inhibits neurons via glycine-gated chloride channels (glycine receptor)
also binds to NMDA glutamate receptors
spatial arrangement of excitatory and inhibitory synapses
inhibitory synapses can block propagation of EPSP toward the soma
GABAa receptors don’t always produce an IPSP e.g. when Vm is near Cl- Nernst potential
instead use shunting inhibition - opening Cl- conductance decreases membrane resistance - current leaks out the membrane
presynaptic inhibition (with GABA)
- action potential arrives at presynaptic terminal
- action potential arrives at same time at GABAergic neuron that synapses onto the presynaptic terminal
- GABA released onto neuron activates GABAb receptors
- inactivates some calcium channels, so less calcium enters
- neuron releases less neurotransmitter
- reduced effect on postsynaptic neuron
acetylcholine - metabolism
ChAT (choline acetyltransferase)- good marker for cholingeric neurons - used to for ACh
acetyl CoA - produced by cellular respiration in mitochondria: acetyl CoA + choline –> ACh
– break down ACh with acetylcholinesterase into acetic acid and choline
ACh - ionotropic and metabotropic receptors
ionotropic:
nicotinic receptors (nAChRs) = ACh gated Na+ and Ca2+ channel in neuromuscular junctions
nicotine (+) and curare (-) can enter neuron
metabotropic:
muscarinic receptors (mAChRs) = 5 types of GPCRs in CNS and ANS:
- M1,3,5 = excitatory via Gq
- M2,4 = inhibitory via Gi/o
muscarine (+) and atropine (-) enter neuron
brain has 10-100x more mAChRs than nAChRs
ACh - substances which affect ACh
block release:
- botox
- black widow spider venom
block AChE :
- nerve gas
- organophosphate pesticides
- Alzheimer’s treatments
activate ACh receptors:
- nicotine, muscarine (+vs)
- neonicotinoid pesticides
block ACh receptors:
- nicotinic = curare (-ve), a-bungarotoxin (snakes)
- muscarinic = atropine (-ve)
ACh - why is atropine used to treat nerve gas poisoning
nerve gas = blocks AChE = ACh isn’t broken down
atropine = blocks muscarinic ACh receptors
as ACh isn’t broken down, it needs to inhibited elsewhere
monoamine synthesis
synthesised from amino acids
catecholamines:
- tyrosine
- dopamine
- norepinephrine
- epinephrine
serotonin (5-HT - 5-hydroxytryptamine)
monoamines - storage and removal
packed into vesicles by vesicular monoamine transporters (VMAT)
removed from synaptic cleft by reuptake transporters (specific for each monoamine)
destroyed by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT - on postsynaptic cell - only for catecholamines (not serotonin))
monoamine - receptors
mostly GPCRs
different receptors activate different G-protein effectors and in different neurons types/brain areas – therefore drugs have specific effects
dopamine = D1-like (D1, D5) & D2-like (D2,D3,D4)
epinephrine, norepinephrine = adrenergic receptors (alpha and beta types)
serotonin = 7 receptors, one is a ligand-gated Na+/K+ channel
dopamine - motor conrol
dopaminergic neurons in substantia nigra project into striatum –> nigrostriatal pathway - facilitates initiation of voluntary movement
DA-ergic neurons die in Parkinson’s (motor dysfunction)
treated by increasing DA:
- TH (tyrosine hydroxylase) is rate limiting in synthesis of dopamine (synthesis of L-DOPA)
- can take L-DOPA - DA doesn’t cross BBB - L-DOPA becomes DA
dopamine - reward
DAergic neurons in ventral tegmental area (VTA) - project to cortex and limbic system
mesolimbic pathway mediates reward/motivation
intracranial self-stimulation of mesolimbic pathway is very rewarding - addiction
noradrenergic neurons - location and function
regulation of arousal
small number in locus coeruleus innervate the whole brain
function = sleep/wake, attention, arousal, mood, memory, anxiety, pain etc.
distinct from role of norepinephrine in ANS
serotonergic neurons - function and location
regulate sleep/wake and mood
in Raphe nuclei - project all over brain
drug effects on monoamines
cocaine, amphetamines = block reuptake of DA and NE
antipsychotics = block DA receptors (Parkinson’s like side effects are possible)
antidepressants = tricyclics (block reuptake of NE & 5-HT); SSRIs (e.g. fluoxetine (Prozac)); MAO-A inhibitors
other neurotransmitters - endocannabinoids
lipid soluble (not in vesicles)
Ca2+ triggers synthesis, not vesicle fusion
retrograde signalling (post –> pre)
bind to GPCRs (targets of active compound in cannabis
other neurotransmitters - opioid peptides
e.g. endorphins
bind to opioid receptors (GPCRs)
regulate pain, coughing, GI tract
opioid receptors are target of morphine, heroin
other neurotransmitters - ATP
often co-transmitter
P2X2 = ATP-gated ion channels
P2Y2 = GPCRs
other neurotransmitters - nitric oxide
gas, membrane permeable
acts on soluble guanylate cyclase (not a membrane receptor)
