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Overview MEDSCI309 > Neuromuscular Junction > Flashcards

Neuromuscular Junction Flashcards

1
Q

A synapse is a

A

specialized area of communication between excitable cells

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2
Q

Electrical Theory

A

Cells are continuous, allowing direct current flow
o Allow bi-directional conduction
o Calcium independent
o Very fast

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3
Q

Evidence against Electrical Theory:

A

• Evidence against:
o Flow of information was unidirectional
o Existence of excitatory as well as inhibitory synapses
o Existence of a delay

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4
Q

Electrical Theory now we know:

A

Some cells are “electrically coupled”
o Gap junctions allow all ions and many small molecules to pass through
( Made up of a pair of hemi-channels, one on eachcell, termed connexons)
Both cells are therefore at the same potential
o Usually between neurons, but important for cardiac AP
propagation

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5
Q

Chemical Theory

A

Discrete presynaptic and postsynaptic cells
• Proposed that presynaptic cells released a chemical that initiated
current flow in the postsynaptic cells

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6
Q

Evidence for Chemical Theory:

A

Strong evidence for came with Otto Loewi’s 2 heart Experiment (1921):
o Parasympathetic (vagus) and sympathetic nerves
released different transmitter substance
which causes different alterations in fH

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7
Q

Further evidence for Chemical Theory: came with advent of electron microscope:

A

§ Pre-synaptic and post-synaptic elements
§ A synaptic cleft
§ Pre-synaptic vesicles

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8
Q

Neuromuscular Junction

A

Space of ~50nm separates the nerve
terminal and the plasma membrane of the
muscle fibre

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9
Q

Neuromuscular Junction Comprised on the

A

basal lamina:

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10
Q

§ In muscle, the ____ _______

supports the Sarcomere Length during contraction

A

basal lamina

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11
Q

Basal lamina contain

A

Collagen IV and laminin (primary glycoproteins),

fibronectin, entactin and perlecan (most abundant proteoglycan)

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12
Q

___ is concentrated (~3,000 per um^2) in the synaptic cleft, and
anchored to the basal lamina

A

AChE

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13
Q

At the muscle, the ______ _____ ramifies into branches about 2um thick swellings
called presynaptic boutons, which are covered by a thin layer of Schwann cells

A

motor axon

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14
Q

‘motor end plate’ is specific for _____ muscle

A

skeletal

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15
Q

The boutons lie over a specialized region of the muscle fibre membrane, the
_______, and are separated from the muscle membrane by a _____ ______

A

endplate

synaptic cleft.

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16
Q

§ Boutons contain:

A

• Hundreds of synaptic vesicles containing the neurotransmitter ACh
• Specialised proteins that regulate the fusion of the vesicles and
the terminal membrane, and release of transmitter from the
active zone

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17
Q

Post-synaptic membrane:

A

The membrane of the folds contains two
distinct domains. At the crests, there is a
high concentration of AchRs (green), the
AChR-clustering protein rapsyn and
utrophin.
§ In the depths of the folds there is a high
concentration of VGSCs (red)

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18
Q

General Mechanism of Synaptic Transmission:

o Presynaptic Events

A

§ AP in the pre-synaptic cell reaches the nerve terminal
§ Depolarisation opens VGCC (transducers) resulting in calcium influx
§ Exocytosis of vesicles and release of neurotransmitter

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19
Q

General Mechanism of Synaptic Transmission:

o Postsynaptic events

A

§ Reaction of transmitter with postsynaptic receptors
§ Activation of synaptic channels to produce a postsynaptic current
§ Change in postsynaptic potential gives rise to a propagated AP in the
post-synaptic cell

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20
Q

Properties of a Neurotransmitter

o Five minimal criteria:

A

§ Substance present in the pre-synaptic nerve terminals
§ Substance is released during depolarization of the pre-synaptic nerve
terminal
§ Effect is mimicked by exogenous application to post synaptic membrane
§ Existence of an inactivation mechanism
§ Antagonists affect the response in a similar manner

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21
Q

Direct-Gated Transmission:
AP in pre-synaptic axon depolarizes the pre-synaptic terminal, opens VGCC.
Ca enters terminal and triggers fusion of vesicles to pre-synaptic active zone
membrane. Opening of the vesicles releases transmitter (via process of
exocytosis) into the synaptic cleft

A

o At the NMJ, ACh diffuses across cleft and binds to AChRs causing them to
undergo a conformation change which then opens the integral ion channel
o Ion flux through AChRs (synaptic of EPC) depolarizes muscle end plate
o Amplitude of EPP depolarizes muscle fibre membrane beyond threshold to
open voltage gated sodium channels and trigger muscle AP
( The Nicotinic ACh-gated Ion Channel)

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22
Q

§ Postsynaptic depolarization caused by EPC is known as the

A

EPP

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23
Q

Indirect Gated Transmission
o Some transmitter receptors do not have integral ion channels
o Such receptors couple to membrane bound G-proteins (termed transducers) in
the neural membrane which in turn are coupled to one or more membrane bound
enzymes (primary effectors).

A

o Second messengers in post-synaptic neuron activate effector proteins (e.g.
protein kinase enzyme) which in turn phosphorylate effector proteins to bring
about a change in the post-synaptic neuron function – often resulting in
modification of ion channel function

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24
Q
  • Transmitter Inactivation and Recycling
    Within the synaptic cleft at the NMJ is a basement membrane composed of
    collagen and other ECM proteins
A

o The enzyme AChE is anchored to the collagen fibrils of the BM
o The enzyme appears to be made by the muscle and deposited in the ECM
o AChE rapidly hydrolyses ACh
Choline then diffuses back to the presynaptic terminal and is reabsorbed
o AChE is the physiological target of insecticides and military nerve gases

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25
Q

End-Plate Current

A

At an end-plate, EPC is generated by the near synchronous opening of more
than 200,000 individual AChR-ion channels, each permitting around 17,000
Na+ ions to enter the muscle EP (and also a smaller number of K+ ions to leave),
so net inward, depolarizing current

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26
Q

o AChE rapidly hydrolyses ACh

Choline then diffuses back to the ________ _________and is reabsorbed

A

presynaptic terminal

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27
Q

o Equivalent Circuit Representing EPC:

A

A circuit can be drawn representing the EP region with 3 parallel
branches:
• 1. A branch representing the flow of synaptic current through
transmitter gated channels
• 2. A branch representing the return current through resting
channels
• 3. A branch representing the current flow across the lipid bilayer

28
Q

Current through synaptic pathway is carried by

A

both Na+ and K+ ions

29
Q

EP Conductance depends on the number of channels open, therefore, in the
absence of transmitter, the conductance is _____
§ Conductance increases to about 5 x 10-6 S when a pre-synaptic AP
causes release of transmitter, i.e. about 5 x the conductance in the branch
representing the resting, or leakage, channels

A

0.

30
Q

§ End-plate conductance is in series with a battery (EEPSP) whose value is
given by the __________ for synaptic current flow (0 mV), i.e. the
algebraic sum of Na and K equilibrium potentials

A

reversal potential

31
Q

End-Plate Potential

The net postsynaptic ……..

A

depolarization produced by the synronised release of Ach

from synaptic vesicles on depolarization of the nerve terminal

32
Q

o EPP amplitude is determined by

A

the number of vesicles released by the nerve AP (50-300 in mammalian NMJ) and their quantal content

33
Q

Characteristics of EPP in skeletal muscle:

A

§ EPP are always supra-threshold
§ Like some EPSPs, the EPP itself travels passively along the postsynaptic cell (muscle fibre in this case) for only a short distance (of the
order of the muscle length constant, a few mm) before dissipating

34
Q

Curare

A

muscle relaxant that blocks the nicotinic acetylcholine receptor (nAChR), one of the two types of acetylcholine (ACh) receptors, at the neuromuscular junction.

35
Q

Spread of the EPP was electronic (i.e. propagation is passive)
• Therefore the EPP can only be recorded at the endplate, since it
is conducted with decrement
• _____are therefore essential for propagation of the AP and the
synchronized contraction of large skeletal muscle fibres, but the
EPP relies on ___________caused by the EPC

A

VGSC

depolarization

36
Q

The EPC and EPP have different time courses:

A

EPC and EPP have different time courses:
• EPC has time course defined by mean open time of AChR
channels (T ms)
• EPP has longer time course defined by both AChR channel open
time and passive electrical charging/discharging time of muscle
membrane (behaves like RC network with characteristic time
constant: t > T)

37
Q

Pharmacological agents used experimentally to study the NMJ

o

A

Alpha toxins: Specific blockers of nicotinic AChRs
o Found in some snake venoms, e.g. alpha-bungarotoxin
o Curare, a plant extract used by some South Amerian Indians arrows to paralyse prey
(An alternative way to do this would be to restrict the calcium
concentration in the solution)

38
Q
  • Quantal Release of Neurotransmitter

o Indications of quantal release of neurotransmitter:

A
  1. Evidence from morphological examination of the synapse

§ 2. Evidence from quantal analysis of experimental data

39
Q

Early experiments observed that when the nerve was stimulated there was a
depolarization in the post-synaptic cell of the order of tens of mV (EPP),
however they also observed that small depolarisations of ~0.5mV occurred in
the absence of nerve stimulation every ~1s

A

MEPPs

40
Q

Under normal conditions, MEPPs do not arise from ?

Fatt and Katz showed that their release was random

A

depolarization of the

presynaptic nerve terminal:

41
Q

Katz showed that ____arose even in a high [K+]o
bathing solution, so that even with the nerve-muscle preparation
depolarized you could still record changes in membrane potential caused
by ____

A

MEPPs

42
Q

Used a fine electrode to deliver a known concentration of ACh
into the synapse and record the voltage change, therefore
determine how much ACh was required to produce the ____
§ They estimated that a single _____was the result of release of about
6000 molecules of ACh

A

MEPPS

43
Q

§ Investigation of whether mEPPs and EPPs were related:

A

• Both EPPs and mEPPs were blocked by curare
• Anti-cholinesterase prolonged the duration of both EPPs and
mEPPs
• The frequency of mEPPs was increased by small depolarisations
in the presynaptic cell

44
Q

Anticholinesterases

A

are a class of drugs that decrease breakdown of acetylcholine

45
Q

Katz had previously notes that 1 EPP was equivalent to

A

~100
simultaneous mEPPs
Katz concluded that the EPP was in fact made up of multiple
mEPPs

46
Q

______is the key molecular trigger for transmitter release

A

Calcium

47
Q

Early work was conducted on the NM synapse and squid giant axon
o At the squid giant synapse, combined intracellular pre-synaptic and postsynaptic
recordings, together with pre-synaptic intracellular electrical
stimulation, are possible due to the ?

A

large size and possibility for visual guidance

of electrode placement

48
Q

Study of the movement of radioactive Ca2+ into the squid axon and the use of
Ca2+ channel blocking agents proved that Ca2+ entry into the pre-synaptic
terminal took place via _____________during _______AP
and was an absolute requirement for transmitter release

A

voltage gated Ca2+ channels

pre-synaptic

49
Q

Del Castillo and Katz showed that reducing [Ca2+]o:

A

§ Reduced the amplitude of the evoked EPP (from ~70mV to as low as
0.5-2.5mV)
§ Produced no change in amplitude of unit responses,
Reduced the number of quanta released

50
Q

Voltage clamp + blocking sodium and potassium channels
§ TEA blocks?
§ TTX blocks ?

A

potassium channels

sodium channels

51
Q

§ Graded depolarisations gave a graded inward calcium current
Resulted in graded post-synaptic membrane
§ Shows that:
•

A

Calcium was essential for transmitter release to take place
• Amount of transmitter release was proportional to the amount of
calcium entering the nerve terminal (but in a non-linear way)

52
Q

Location of calcium receptor

§ Calcium chelators (small molecules that bind very tightly to metal ions).of different binding kinetics used to show

A

that the

calcium binding/trigger is close to the release site

53
Q

_____ _______ ______can be used to record the fusion pore current:

A

Patch clamp techniques

54
Q

Steps in Vesicle Cycling

A 
1. Restrain and mobilization
Targeting to active zone
Docking at the active zone
Fusion & exocytosis
Retrieval of the fused membrane
55
Q

Rhythmic respiratory activity drive to the diaphragm via the

A

phrenic nerve

56
Q

phrenic nerve

A

Rhythmic respiratory activity drive to the diaphragm via the

57
Q

EPP and EPSC associated with the respiratory drive are mediated by

A

glutamate

58
Q

Pattern of EPSPs determine the pattern of

A

AP generation

59
Q

Pattern of AP generation determines

A

contractile function

60
Q

Change in neuronal excitability induced by

A

neuromodulation

which will change pattern of acitivity

61
Q

When a nerve impulse arrives at a noradrenaline nerve terminal, noradrenaline is released from synaptic vesicles into the synaptic cleft. Noradrenaline molecules bind to?
and the nerve impulse is ?

A

their receptors on the post-synaptic membrane and the nerve impulse is propagated or inhibited, depending on the specific receptor

62
Q

Experimental Techniques to study the EPP

{

A

Normally we are thinking about voltage-gated channels, which we can study
by depolarizing them
Voltage clamp of the post-synaptic muscle fibre

63
Q

How are ligand-gated channels studied (AChR is a ligand-gated channel)?
§ A number of ways agonists can be applied to the end-plate region in
vitro

A
  1. A single nerve impulse
    § 2. Spontaneous quantal release
    § 3. Agonist applied in bathing solution
    § 4. Patch of channel with agonist in the patch pipette
    § 5. Flash photolysis of synthetic agonist molecules
64
Q

Note: In order to examine the EPP or EPC under voltage clamp, it is
necessary to either stimulate the motor axon, or to apply an agonist.. Voltage clamp of the post-synaptic muscle fibre
§ Controls the voltage across the membrane
§ Experimental technique

A

Two microelectrodes inserted at the motor end-plate
• (i) Measures membrane potential
• (ii) Passes current
• Both electrodes are connected to a feedback amplifier that
matches the current delivered so that Vm is clamped at the
command vol 0mVtage

65
Q

Unlike the Na+ and K+ channels that underlie the AP, the AChR channel
has a reversal potential at

A

0mV

66
Q

Individual ion channels open and contribute discrete increments of ___
§ EPC rises sharply at start as ___ channels opened in near synchrony
by the wave of synaptically released ACh
§ Channels automatically close as ACh rebinds, and is removed from the
EP
§ Removal of ACh is accelerated bu the enzyme ____
§ AChR channels remain open for variable times

A

EPC
AChR
AChE

67
Q

The total EPC is the sum of

A 
all individual channel currents:
𝑁 = 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐ℎ𝑎𝑛𝑛𝑒𝑙𝑠 𝑖𝑛 𝐸𝑃
§ 𝑝o = 𝑝𝑟𝑜𝑏𝑎𝑏𝑙𝑖𝑙𝑖𝑡𝑦 𝑜𝑓 𝑐ℎ𝑎𝑛𝑛𝑒𝑙𝑠 𝑏𝑒𝑖𝑛𝑔 𝑜𝑝𝑒𝑛
§ 𝛾 = 𝑠𝑖𝑛𝑔𝑙𝑒 𝑐ℎ𝑎𝑛𝑛𝑒𝑙 𝑐𝑜𝑛𝑑𝑢𝑐𝑡𝑎𝑛𝑐𝑒
§ 𝑉 = 𝑚𝑒𝑚𝑏𝑟𝑎𝑛𝑒 𝑝𝑜𝑡𝑒𝑛𝑡𝑖𝑎𝑙
§ 𝐸 epsp = 𝐶ℎ𝑎𝑛𝑛𝑒𝑙 𝑟𝑒𝑣𝑒𝑟𝑠𝑎𝑙 𝑝𝑜𝑡𝑒𝑛𝑡𝑖𝑎𝑙

Overview MEDSCI309 (13 decks)

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