Synapse Flashcards
postsynaptic density
protein dense specialization attached to the postsynaptic membrane
gap junctions consist of:
one connexon consisting of 6 connexin subunits (4 transmembrane domains) on both the pre- and post-synaptic membrane
coupling coefficient
a measure of how well current travels from cell to cell
coupling coefficient = response measured in postsynaptic cell/response measured in presynaptic cell (1=perfect coupling, 0=no coupling)
electrical coupling
a way to synchronize neurons with one another to form neural networks, lower frequency signals couple better than high frequency ones
what are 3 main advantages of chemical synapses?
1) amplification
2) variety of end effects
3) probability of transmission (not 100% faithful)
amplification
a decaying electrical signal is transformed into the release of diffusible molecules, amplification can occur by:
- release of numerous transmitter molecules
- binding to many receptors
variety of end effects
- a synapse can be excitatory or inhibitory
- can activate an ionotropic or metabotropic receptor
- a range of relatively fast to slow effects
- more points for modulation as there are numerous proteins and steps involved
probability of transmission (not 100% faithful)
for every action potential invading a terminal, there is not always release of neurotransmitter. this introduces a bit of randomness into the system, and is thought to be important for varied outputs from a neural circuit
cholinergic synapses
- fast, excitatory
- postsynaptic nicotinic ACh receptors
- ex. neuromuscular junction (NMJ)
glutamatergic synapses
- fast, excitatory
- postsynaptic AMPA and NMDA receptors
- ex. central nervous system (CNS)
GABAergic synapses
- fast, inhibitory
- postsynaptic GABA-A receptors
- ex. central nervous system (CNS)
curare
antagonist of nicotinic AChRs, competes with ACh for binding site, prevents end plate potential from reaching threshold of action potential
junctional folds
deep indentations in the endplate of a neuro-muscular junction, contain high numbers of ligand-gated ion channels for ACh
endplate potential
has an amplitude of 70mV which is very large and passes threshold potential
what determines the rapid rise and decay of end-plate current?
the rapid opening and closing of the ACh receptor channel
why does the EPSP (end plate potential) lag behind synaptic current?
the synaptic current must first alter the charge on the membrane capacitance of the muscle before the muscle membrane is depolarized to produce an EPSP
TTX (tetrodotoxin)
voltage-gated sodium channel blocker
the size of presynaptic depolarization (related to the action potential) controls:
the magnitude of transmitter release (and consequently magnitude of EPSP) (a presynaptic spike less than 40mV fails to produce an EPSP)
what is the presynaptic action potential required to produce a postsynaptic potential?
40mV
what is the relationship between the presynaptic spike and EPSP?
logarithmic: a 10mV increase in the presynaptic spike produces a 10-fold increase in the EPSP
is presynaptic sodium influx (i.e. voltage-gated sodium channels) necessary for transmitter release?
No, can still induce EPSP with current injection through a microelectrode beyond a threshold of 40mV positive to the resting potential even after blocking voltage-gated sodium channels with TTX
tetraethylammonium (TEA)
blocks voltage-gated potassium channels
what is the effect of blocking presynaptic voltage-gated potassium and sodium channels? (TTX + TEA)
presynaptic depolarization is maintained throughout the current pulse, large sustained presynaptic depolarization produces large sustained EPSPs
what is the effect of decreasing extracellular Ca2+ concentration on transmitter release?
lowering the concentration reduces and ultimately blocks synaptic transmission, extracellular Ca2+ must enter the cell to influence transmitter release
the amount of transmitter release is a function of the concentration of:
Ca2+ in the presynaptic terminal
Calyx of Held
a large synapse in the mammalian brain stem that is part of the auditory pathway
synaptic delay
1-2ms delay between the onset of presynaptic action potential and the excitatory postsynaptic potential
what is an important determinant for the amount of Ca2+ influx into the presynaptic cell?
the duration of the action potential
what accounts for synaptic delay?
the time required to open voltage-gated Ca2+ channels (open slowly, once presynaptic membrane has begun to repolarize), once calcium enters cells, vesicle release occurs very rapidly as the biochemical machinery underlying the release process exists in a primed and ready state and because calcium channels are located very closely to the vesicle. Ca2+ channels are also only open for a short time
active zones
the sites were neurotransmitter is released in the presynaptic terminal, directly opposite the postsynaptic receptors. calcium ion channels are concentrated here
calcium nanodomain
found in the active zone; a single Ca2+ channel opens on a cell membrane, allowing an influx of Ca2+ ions which extend a few tens of nanometers from the channel pore. The coupling distance is very small (less than 100nm) which allows rapid signalling. nanodomain collapses quickly when calcium channel closes, as the ion rapidly diffuses away from the pore; nanodomains from adjacent calcium channels do not overlap
coupling distance for calcium
the distance between the calcium-binding proteins which sense the calcium, and the voltage-gated presynaptic calcium channels
why do calcium ions not diffuse far from their site of entry in the presynaptic terminal?
because free calcium ions are rapidly buffered by calcium-binding proteins
omega conotoxin
presynaptic calcium channels
alpha and psi conotoxin
block postsynaptic ACh receptors
Mu conotoxin
blocks sodium channels to prevent muscle action potential
conotoxins
act on the neuromuscular junction and causes paralysis
miniature endplate potentials (mEPPs)
occur spontaneously, not caused by a natural or experimentally evoked action potential, represent responses to small packets of transmitter that are spontaneously released from the presynaptic nerve terminal in the absence of an action potential, do not cause action potentials (don’t reach threshold)
prostigmine
a drug that blocks hydrolysis of ACh by acetylcholinesterase, enhances and prolongs EPPs and mEPPs
one quantum
the smallest amount of stimulation that one neuron can send to another neuron, discrete size based on amount of transmitter packed in vesicles
how many channels are open during a single mEPSP?
2000 channels (2 transmitters bind to open one receptor)
how many transmitters are contained in a single vesicle at the end-plate presynaptic terminal?
about 5000 transmitters
what is the effect on postsynaptic membrane potential if a motor neuron is stimulated in low calcium solution?
the amplitude of voltage change is about the same as spontaneous mEPP because calcium is required for neurotransmitter release
spontaneous mEPP
mEPP occurring at random intervals, same size as the unit potential (i.e. one vesicle released/smallest EPP of motor neuron stimulated in low calcium solution)
the amplitude of each end-plate potential is an integral multiple of:
the unit potential / mean amplitude of mEPPs (which has a relatively tight, unimodal distribution and represents the transmitter released in single packets)
the end plate potential is made up of the aggregated sum of:
many mEPPs. a normal end plate potential will usually cause the neuron to reach its threshold of excitation and elicit an action potential
v-SNARE
synaptobrevin (vesicle associated membrane protein/VAMP), located on each synaptic vesicle
t-SNARE
syntaxin (transmembrane protein) and SNAP-25 (peripheral protein), located on presynaptic active zone, during exocytosis, v-SNARE forms a tight complex with t-SNARES on the plasma membrane
how does fusion of the synaptic vesicle and plasma membrane occur?
by formation of SNARE complex, extraordinarily stable and releases large assembly (allows negatively charged phospholipids of vesicle to draw close to plasma membrane and form a pre-fusion intermediate state)
Munc-18
protein required for exocytosis of synaptic vesicles, binds to syntaxin before the SNARE complex assembles. deletion of Munc-18 prevents all synaptic fusion in neurons
synaptotagmin
membrane protein on vesicle that serves as the calcium sensor for exocytosis
synapsin
peripheral vesicle protein that regulates the availability of vesicles from the reserve pool (mobilization)
NSF and SNAP
two proteins that bind to the SNARE complex following fusion with membrane (after calcium influx) and causes it to dissociate in an ATP-dependent reaction from the fusing vesicle
how does the neuron prevent the supply of vesicles from being rapidly depleted?
used vesicles are rapidly retrieved and recycled via endocytosis
why aren’t vesicles replenished by synthesis in the cell body?
nerve terminals are usually some distance from the cell body; synthesis in the cell body and transport to the terminals would be too slow to be practical
the synaptic vesicle cycle
1) vesicles fill with neurotransmitter by active transport
2) vesicles cluster in the nerve terminal and form a reserve pool
3) filled vesicles dock at the active zone
4) following an ATP-dependent priming reaction, they are able to respond to the calcium signal that triggers the fusion process
5) fusion
6) after discharging their contents, synaptic vesicles are recycled through one of several routes
4 criteria to be recognized as a neurotransmitter:
1) synthesized in the presynaptic neuron
2) present in the presynaptic terminal and is released in amounts sufficient to exert a defined action on the postsynaptic neuron or effector organ
3) when administered exogenously in reasonable concentrations, it mimics the action of the endogenous transmitter
4) a specific mechanism usually exists for removing the substance from the synaptic cleft
glutamate
major excitatory neurotransmitter in the brain
GABA
major inhibitory neurotransmitter in the brain
are there more excitatory or inhibitory synapses?
more excitatory synapses
acetylcholine
peripheral motor neurons, autonomic neurons, central neurons, arousal
serotonin
mood
dopamine
movement, goals and reward
noradrenaline
autonomic neurons, central neurons for attention, arousal
synthesis of catecholamines
dopamine/norepinephrine/epinephrine are all synthesized from the essential amino acid tyrosine in a common biosynthetic pathway
dopamine transporter, norepinephrine transporter, serotonin transporter
located on presynaptic nerve terminal or surrounding glial cells, terminates signal and recycles transmitter (driven by sodium gradients = sodium influx)
vesicular monoamine transporter
driven by H+ gradient (H+ efflux), transports all 3 monoamines into synaptic vesicles for subsequent exocytotic release
monoamine oxidase
degrades DA, NE, and SERT in the synaptic cleft
acetylcholinesterase
terminates cholinergic signaling by degrading ACh into choline and acetate in the synaptic cleft
choline
transported back into presynaptic terminal by choline transporter CHT (driven by sodium influx)
choline acetyltransferase (ChAT)
catalyzes the acetylation of choline (choline + acetyl-CoA) to form ACh in the presynaptic terminal
vesicular ACh transporter (VAChT)
transports ACh into the vesicle (driven by H+ efflux)
GLT/GLAST
glutamate transporters on surrounding glial cells
SN1/SN2
proteins on glial cells that transport glutamine out to the neuron, driven by sodium efflux and proton influx
SAT (SATx)
protein on presynaptic membrane, transports glutamine into presynaptic neuron, driven by sodium influx
glutamine synthetase
in glial cells, glutamate is converted back to glutamine
phosphate-activated glutaminase
converts glutamine back to glutamate in the presynaptic terminal
VGLUT1/-2/-3
transports glutamate into vesicles, driven by H+ efflux
GLT
glutamate transporter, transports glutamate back into presynaptic terminal, driven by sodium influx
GABA transporter (GAT1)
on presynaptic terminal, mediates the reuptake of GABA, driven by sodium influx
GAT3
on glial cells, uptake of GABA, driven by sodium influx
GABA transaminase
in glial cells, converts GABA to glutamate, and glutamine synthetase then converts glutamate to glutamine (uses SN1/SN2 and SATs to transport glutamine back to neuron)
system N transporter
SN1/SN2
system A transporter
SAT
glutamate decarboxylase
converts glutamate to GABA in presynaptic terminal
what does the action of a transmitter depend on?
the properties of postsynaptic receptors that recognize and bind the transmitter, not on the chemical properties of the transmitter
what are 2 features common to all receptors for chemical transmitters?
1) membrane-spanning proteins
2) carry out an effector function within the target cell
ionotropic receptors
- aka direct gating receptors, receptor-channels, ligand-gated channels
- conformation change when bound to neurotransmitter that opens the channel
- 4-5 subunits
metabotropic receptors
- 1-2 subunits
- activation stimulates production of second messengers which can activate protein kinases that indirectly phosphorylate ion channels and lead to their opening or closing
- indirect gating receptors
nicotinic acetylcholine receptor
- ionotropic
- binds 2 ACh
- permeable to both sodium (influx) and potassium (efflux)
- 5 subunits (1 subunit has 4 transmembrane domains M1-M4)
why is the reversal potential of the end-plate potential due to nAChR 0mV?
reflects the weighted average of the equilibrium potential for sodium and potassium
glutamate receptors
(most abundant receptors in the brain) ionotropic: AMPA, Kainate, NMDA
metabotropic
ionotropic glutamate receptors
-comprised of different combinations of different subunits (7 for NMDAr, 4 for AMPAr)
metabotropic glutamate receptors
not composed of different subunits, a single,complete, receptor
AMPA receptor
- the main synaptic depolarizing force the brain
- located postsynaptically
- 4 different subunits (Glur1-4) per channel
- usually Ca2+ -impermeable, can pass Na+ and K+
NMDA receptors
- located postsynaptically with AMPAR
- permeable to Na+, K+, and Ca2+
- 5 subunits per channel
- requires 2 NR1 and a type of NR2 subunit (NR2A-D)
- different subunit combinations affect channel kinetics
subunit function of NR1 (NMDAR)
glycine/d-serine binding site (co-agonist)
subunit function of NR2 (NMDAR)
glutamate binding site (ligand)
subunit function of NR3 (NMDAR)
“attenuating” function, channels containing NR3A have a smaller unitary conductance, shorter open time, and lower Ca2+ permeability
coincidence detection of NMDA receptor
opening depends on membrane depolarization (postsynaptic activity via AMPA receptor opening) to remove Mg2+ block + glutamate binding
at most glutamatergic synapses, AMPA receptors are capable of triggering an action potential, what is the function of NMDA receptors?
NMDA receptors conduct Ca2+ and increase intracellular Ca2+ that can activate various calcium-dependent signaling cascades (including calcium-calmodulin-dependent protein kinase II, CAMKII): thus NMDA receptor activation can translate electrical signals into biochemical ones
biochemical effects of NMDA receptor activation can lead to:
long-lasting changes in synaptic strength/plasticity (e.g. long term potentiation, depression of synaptic strength due to differential activation of NMDA receptors)
APV
NMDA receptor antagonist, when added, it only shows the NMDA component of the current which doesn’t come on until depolarized potentials due to the Mg2+ block when hyperpolarized
synthesis of GABA requires which enzyme?
glutamic acid decarboxylase (GAD)
which enzyme is involved in the metabolism of GABA?
GABA transaminase (GAT)
GABAA receptor
- permeable to Cl- cause cell hyperpolarization (Vm/reversal potential for Cl- is -60)
- 5 or 6 different subunits, usually a pentamer with 2 alpha, 2 beta, 1 gamma
- possess binding sites for anti-epileptic drugs, sedatives, and anaesthetics
