Week 4: Synaptic Transmission Flashcards
(19 cards)
Explain the structure and function of the NMJ
The NMJ or neuromuscular junction/end plate is the interface between a presynaptic axon terminal and a region of muscle. The presynaptic terminal contains many vesicles with acetylcholine (ACh) that line up to relase at the active zone. These form rows, and the single vesicles/packets are called quanta. The postsynaptic membrane has acetylcholine receptors (AChR) at a massive density. They also have junctional folds that increase the surface area over which AChRs are spread. The basal membrane that links the NMJ elements contains an enzyme called Acetylcholinesterase (AChE) that will hydrolyze ACh to choline and acetic acid, terminating the function of the signaling molecule. Reuptake of choline for reactivation and recycling is modulated by channels on the surface of the presynaptic axon terminal. Choline and acetic acid are rejoined to form ACh by an intracellular enzyme called ChAT (choline acetyltransferase)
What does ACh do at the end plate as it relates to signal transduction?
ACh can activate the Na+/K+ ion channel that allow for influx of ions across the membrane. This can depolarize the muscular region that interacts with the presynaptic axon terminal, and initiate muscular contraction via a Ca2+-mediated process.
What are the two receptor types found in the junctional folds, and how are they activated? Once activated, what happens?
Ionotropic
- Stim by nicotine, attached to an ION channel, 2 ACh molecules bind to one receptor
- found on NMJ, causes rapid desensitization
Metabotropic
- Stim by muscarine, attached to a G-protein, 2 ACh molecules bind to receptor
- Located throughout body but NOT at NMJ
Explain the breakdown and reuptake of ACh in the synaptic cleft
ACh is broken down in the cleft by acetylcholinesterase (AChE). This allows for a shortening of the ACh signal. Then, the acetic acid and choline are taken back into the presynaptic membrane and converted back into ACh by ChAT (cholineacetyltransferase). These are then pumped back into vesicles via a H+/ACh ATPase proton pump, moving H+ into the presynaptic membrane and ACh into vesicles
What are antagonists against the AChR?
Curare - competitive antagonist that is reversible, used in surgery
a-bungarotoxin - competitive antagonist that is irreversible, cannot be overcome–found in cobra toxin
What is myasthenia gravis and how does it arise?
Autoimmune disease in which antibodies develop and block the AChR, preventing ACh from binding to it’s receptor
Therapy: block AChE to prevent ACh hydrolysis, giving ACh more time to act in the synaptic cleft
Describe exitation-secretion coupling
(1) Presynaptic cell undergoes a standard AP (excitation)
(2) V-gated Ca2+ channels open, Ca2+ enters the axon terminal
(3) Ca2+ concentration increase causes vesicles containing the ACh to migrate towards the membrane and fuse, leading to exocytosis of ACh (secretion)
(4) ACh binds to nicotinic receptor, opening ligand-gated ion channel, causing Na+ influx
(5) Potential reaches/exceeds threshold, generating an all-or-none AP via voltage-gated ion channels
What are some characteristics of an end-plate potential?
When the AP in the nerve reaches the pre-synaptic terminal, the AP proceeds as normal–however, then Ca2+ rushes in, causing an inversion in the AP. The current is inward (negative) because a 2+ charge is flowing INTO the cell–length of the AP determines the amount of presynaptic inward Ca2+ current. This is because the membrane is depolarized for a longer period, so Ca2+ channels are open longer. The amount of Ca2+ in the presynaptic terminal determines the amount of ACh released.
Binding of ACh to it’s receptor causes Na+ flux into the post-synaptic cell, forming the EPSP shown in the figure. When enough Na+ fluxes inwards, the threshold is reached (safety factor ensures this) to stimulate the depolarization of the target muscle.
What is the difference between an action potential and an EPP?
The AP is all-or-none but the EPP is graded. EPP is totally dependent on the amount of ACh released, but the safety factor helps ensure that the threshold is reached nearly every time ACh is released into the cleft.
What determines the EPP amplitude?
(1) Strength of Ca2+ current in presynaptic cell
(2) Number of vesicles in the synapse
(3) Concentration of ACh in the vesicle
(4) Concentration of AChR receptors available on the postsynaptic membrane
What is the peak threshold value at the AChR, and what is the general structure and function of the related channel?
The peak threshold is 0 mV, which is right between the ENa of +90 mV and the EK of -90 mV. The ion channel in muscle cells is almost equally permeable to both Na+ and K+ ions. As such, the resting potential is equal to the point of equal flux by both ions, which is 0 when you take an average of the two.
What are the general characteristics of the AP?
(1) Mediated by two v-gated channels (K+ and Na+)
(2) Rapid depolarization with an overshoot to +40 mV
(3) Charge is mostly mediated by Na+
(4) Repolarization is due to increased permeability to K+ and inactivation of Na+ channels
(5) Two independent channels–one K+ and one Na+
What are the general characteristics of the EPP?
(1) Mediated by one ligand-gated channel (AChR)
(2) Rapid depolarization with overshoot to 0 mV
(3) Charge is carreid by both Na+ and K+ with Erev = EK + ENa/2
(4) Passive repolarization mediated by a leak channel
(5) Single channel is permeable to both Na+ and K+
What is the difference between quantal size and quantal content?
Quantal size is the size of the depolarization response to the quantal release (i.e. how much does the end plate membrane depolarize due to the release of the contents of one vesicle?)
Quantal content corresponds to the content of vesicles (amount/number of quanta) released by the presynaptic nerve
What are some of the ways Ca2+ is sequestered either within a cell, or how it’s intracellular concentration is reduced?
Binding: Reduce the amount of free intracellular calcium through binding to intracellular proteins (calmodulin, synaptotagmin, etc.)
Sequestration: Transport calcium into organelles using transport proteins
- mitochondria: mitochondrial calcium uniporter
- smooth ER: Ca2+ ATPase
(outbound: ryanodine/IP3 receptor in ER causes calcium to move into the cytoplasm)
Extrusion: Ca2+ ATPase pump out of cell membrane, Na+/Ca2+ exchange of Ca2+ ion against it’s concentration gradient while Na+ moves ALONG it’s concentration gradient
What are the characteristics of Ca2+ L-Type channels?
L = long-lasting, becomes activated at higher membrane potentials
Slow-opening, but remain open longer
Inactivated by Dihydropyridines
Many locations in skeletal/cardiac muscle and brain
What are the characteristics of P/Q type Ca2+ channels?
P = Purkinje, Q = no meaning
High threshold of activation
P-Type present in presynaptic terminal of NMJ, responsible for ACh release
Not sensitive to DHP, inactivated by spider venom
What are the characteristics of the N-Type Ca2+ channel?
N = neuronal
Similar to the P/Q type, involved in NT release
Also involved in Ca2+ homeostasis
Deactivated by conotoxin
What are the characteristics of the T-Type Ca2+ channel?
T = transient
Activated at RP, usually before L-Type, T-Type helps initiate the AP whereas L-Type helps sustain it
Important in cardiac electrophysiology
