Chapter 7: Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling Flashcards

1
Q

Where in the spinal cord do the myelinated nerve fibers that innervate skeletal muscle originate from?

A

Large motor neurons in the anterior horn of the spinal cord

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2
Q

Each nerve ending makes a junction, called the _______, with the muscle fiber near its midpoint

A

neuromuscular junction

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3
Q

These are the neuroglia found at the Neuromuscular junction (NMJ) with known functions in synaptic transmission, synaptogenesis, and nerve regeneration.

A

Perisynaptic Schwann cells or Terminal Schwann cells or Teloglial cells

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4
Q

What is the structure on the surface of the muscle fiber invaginated by branching nerve terminals that lie outside the muscle fiber plasma membrane?

A

Motor end plate

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5
Q

These cells insulate the motor end plate from the surrounding fluids

A

Schwann cells (perisynaptic or terminal Schwann cells or Teloglial cells)

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6
Q

The invaginated membrane of the motor endplate is called the:

A

synaptic gutter or synaptic trough

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7
Q

What do you call the space between the axon terminal and the fiber membrane?

A

Synaptic cleft or synaptic space

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8
Q

What is the width of the synaptic cleft?

A

20 to 30 nanometers

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9
Q

These are numerous smaller folds of the muscle membrane which greatly increase the surface area of at which the synaptic transmitter can act

A

subnerural clefts

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10
Q

What is the function of the numerous mitochondria at the axon terminal?

A

They supply ATP, the energy source used for synthesis of a transmitter, acetylcholine, which excites the muscle fiber membrane.

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11
Q

What enzymes, which destroys the transmitter released from the synaptic vesicles, are present in large quantities in the synaptic space?

A

Acetylcholinesterase

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12
Q

Approximately how many synaptic vesicles of ACh are released from the terminals into the synaptic space during a nerve impulse?

A

125 vesicles

**About 125 vesicles usually rupture with each action potential.

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13
Q

On the inside surface of the neural membrane are linear dense bars. What are the protein particles, found to each side of each dense bar, penetrating the neural membrane and allows Ca++ to diffuse when action potential spreads over the terminal?

A

Voltage-gated protein channels

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14
Q

Which enzyme is activated by the calcium ions that diffuse to the interior of the nerve terminal upon the spread of action potential?

A

Calcium-calmodulin-dependent kinase

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15
Q

The Calcium-calmodulin-dependent protein kinase phosphorylates which protein in the nerve terminal?

A

Synapsin

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16
Q

These are proteins that anchor the acetylcholine vesicles to the cytoskeleton of the presynaptic terminal

A

Synapsin

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17
Q

Where do the acetylcholine vesicles move to upon the phosphorylation of synapsin?

A

active zone

The phosphorylation of synapsin frees the acetylcholine vesicles from the cytoskeleton and allows them to move to the active zone of the presynaptic neural membrane adjacent to the dense bars.

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18
Q

The process by which the presynaptic vesicles empty their acetylcholine into the synaptic space

A

exocytosis

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19
Q

What is the effective stimulus for causing acetylcholine release from the presynaptic vesicles?

A

entry of calcium ions

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20
Q

Which ion channels are located almost entirely near the mouths of the subneural clefts lying immediately below the dense bar ares?

A

acetylcholine-gated ion channels

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21
Q

What is the total molecular weight on an ACh receptor?

A

275,000

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22
Q

Which subunit proteins make up the FETAL acetylcholine receptor complex?

A

2 alpha protein and one each of beta, delta, and gamma proteins

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23
Q

What charges are present at the acetylcholine-gated channels?

A

Negative charges

**prevents passage of negative ions such as chloride

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24
Q

Which protein subunit substitutes for the gamma protein in the adult acetylcholine receptor complex?

A

Epsilon

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25
Q

To which subunits of the acetylcholine receptor do ACh molecules attach and cause conformational change that opens the channel?

A

2 alpha subunits

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26
Q

What is the diameter of the ACh-gated channel that allows the passage of positive ions like Na+, K+ and Ca2+?

A

0.65 nanometer

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27
Q

The Ach-gated channels allow passage of different positively charged ions. What are the 2 reasons that allow the flow of far more sodium ions compared to other cations?

A

(1) only sodium and potassium ions are present in large concentrations
(2) the negative potential inside the muscle membrane, -80 to -90 mV, pulls the positively charged sodium ions to the inside of the fiber while simultaneously preventing efflux of the positively charged potassium ions when they attempt to pass outwards

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28
Q

This refers to the positive potential change inside the muscle fiber membrane caused by the entry of sodium ions upon the opening of Ach-gated channels?

A

End plate potential

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29
Q

What causes the sufficient depolarization of the sarcolemma that allows even greater sodium ion inflow and initiating an action potential spread along the muscle membrane?

A

End plate potential

** Cause by the opening of ACh-gated channels allowing entry of Na+

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30
Q

This enzyme is attached mainly to the spongy layer of fine connective tissue that fills the synaptic space between the presynaptic nerve terminal and the postsynaptic muscle membrane

A

Acetylcholinesterase

31
Q

The local end plate potential increases to the positive direction to as much as _________ upon the insurgence of sodium causing more sodium channels to open.

A

50-70 mV

**The sudden insurgence of sodium ions into the muscle fiber when the acetylcholine-gated channels open causes the electrical potential inside the fiber at the local area of the end plate to increase in the positive direction as much as 50 to 75 millivolts, creating a local potential called the end plate potential. Recall from Chapter 5 that a sudden increase in nerve membrane potential of more than 20 to 30 millivolts is normally sufficient to initiate more and more sodium channel opening, thus initiating an action potential at the muscle fiber membrane

32
Q

This drug causes weakening of the endplate potential by competing for the ACh receptor sites thereby blocking the gating action of the transmitter

A

Curare

33
Q

This bacterial toxin weakens the endplate potential by decreasing the quantity of acetylcholine release by the nerve terminals. It does this by cleaving target proteins of the SNARE complex

A

Botulinum toxin

34
Q

Which of botulinum toxic serotypes cleave the synaptobrevin-VAMP (vesicle-associated membrane protein)?

A

Serotypes B, D, F, and G

35
Q

Which botulinum toxin serotypes cleave the SNAP-25 (25kD synaptosome-associated protein)?

A

Serotypes A and E

36
Q

This refers to the ability of neuromuscular transmission to remain effective under various physiological conditions and stresses

A

Safety factor

**Ordinarily,
each impulse that arrives at the neuromuscular junction causes about three times as much end plate potential as that required to stimulate the muscle fiber. Therefore, the normal neuromuscular junction is said to have a high safety factor.

37
Q

This situation occurs when the stimulation of the nerve fiber reaches rates greater than 100 times per second for several minutes diminishing the number of ACh vesicles so much that impulses fail to pass into the muscle fiber.

A

Fatigue of the NMJ

38
Q

The small vesicles that store ACh are formed by the Golgi apparatus of which cells?

A

Motor neuron in the spinal cord

**Small vesicles, about 40 nanometers in size, are formed by the Golgi apparatus in the cell body of the motoneuron in the spinal cord. These vesicles are then transported by axoplasm that streams through the core of the axon from the central cell body in the spinal cord all the way to the neuromuscular junction at the tips of the peripheral nerve fibers. About 300,000 of these small vesicles collect in the nerve terminals of a single skeletal muscle end plate.

39
Q

The small vesicles that store ACh are formed by the Golgi apparatus of which cells?

A

Motor neuron in the spinal cord

**Small vesicles, about 40 nanometers in size, are formed by the Golgi apparatus in the cell body of the motoneuron in the spinal cord. These vesicles are then transported by axoplasm that streams through the core of the axon from the central cell body in the spinal cord all the way to the neuromuscular junction at the tips of the peripheral nerve fibers. About 300,000 of these small vesicles collect in the nerve terminals of a single skeletal muscle end plate.

40
Q

Acetylcholine is synthesized in the cytosol of which part of the nerve?

A

nerve fiber terminal

**Acetylcholine is synthesized in the cytosol of the nerve fiber terminal but is immediately transported through the membranes of the vesicles to their interior, where it is stored in highly concentrated form—about 10,000 molecules of acetylcholine in each vesicle.

41
Q

Acetylcholinesterase splits the ACh into _____ and _____.

A

Acetate ion and choline

42
Q

After the cleavage by Acetylcholinesterase, which component of acetylcholine is reabsorbed?

A

Choline

43
Q

Which proteins, attached in the areas of the original vesicles in the terminal nerve membrane, contract and cause the coated pits to break away into the interior of the membrane, forming new presynaptic vesicles for ACh?

A

Clathrin

44
Q

Give 3 drugs that stimulate the muscle fiber by ACh-like action

A

Methacholine
Carbachol
Nicotine

**The main differences between these drugs and acetylcholine are that the drugs are not destroyed by cholinesterase or are destroyed so slowly that their action often persists for many minutes to several hours.

45
Q

What is the mechanism of action in the NMJ of the drugs neostigmine and physostigmine causing muscle spasm?

A

Inactivation of Acetylcholinesterase

**The inactivation of acetylcholinesterase in the synapses no longer hydrolyzes acetylcholine. Therefore, with each successive nerve impulse, additional acetylcholine accumulates and stimulates the muscle fiber repetitively. This activity causes muscle spasm when even a few nerve impulses reach the muscle.

46
Q

This state of the muscle is expected to occur with the action of drugs like nicotine, carbachol and methacholine in the muscle fiber membrane.

A

muscle spasm

**The drugs work by causing localized areas of depolarization of the muscle fiber membrane at the motor end plate where the acetylcholine receptors are located. Then, every time the muscle fiber recovers from a previous contraction, these depolarized areas, by virtue of leaking ions, initiate a new action potential, thereby causing a state of muscle spasm.

47
Q

What cause of death can result from the inhalation of the gas poison diisopropyl fluorophosphate?

A

Laryngeal spam that can cause suffocation of the individual

**Diisopropyl fluorophosphate inactivates acetylcholinesterase for weeks, which makes this poison particularly lethal

48
Q

Give 3 drugs that stimulate the NMJ by inactivating the Acetylcholinesterase

A

Neostigmine
Physostigmine
Diisopropyl fluorophosphate

**Neostigmine and physostigmine combine with acetylcholinesterase to inactivate the acetylcholinesterase for up to several hours, after which these drugs are displaced from the acetylcholinesterase so that the esterase once again becomes active. Conversely, diisopropyl fluorophosphate, which is a powerful nerve gas poison, inactivates acetylcholinesterase for weeks

49
Q

This group of drugs can prevent the passage of impulses from the nerve ending into the muscle.

A

Crurariform drugs

50
Q

This curariform drug blocks the action of acetylcholine on the muscle fiber ACh receptors, thus preventing sufficient increase in permeability of the muscle membrane channels to initiate an action potential.

A

D-tubocurarine

51
Q

This condition is believed to be an autoimmune disease that block or destroy their own acetylcholine receptors that block or destroy their own acetylcholine receptors at the postsynaptic neuromuscular junction.

A

Myasthenia Gravis

52
Q

What is the usual cause of death in patients with Myasthenia gravis?

A

Respiratory failure as a result of severe weakness of the respiratory muscles

53
Q

Which drug can be administered to ameliorate the symptoms of Myasthenia gravis for several hours by allowing larger than normal amounts of acetylcholine to accumulate in the synaptic space?

A

neostigmine and other acetylcholinesterase drugs

54
Q

What is the resting membrane potential of skeletal fibers?

A

-80 to -90 mV

about 10-20 more negative than in neurons

55
Q

What is the normal duration of the action potential in skeletal muscles?

A

1-5 milliseconds

about 5 times as long as in large myelinated nerves

56
Q

What is the normal velocity of conduction of skeletal fibers?

A

3-5 m/sec

about 1/3 the velocity of conduction in the large myelinated nerve fibers that excite skeletal muscles

57
Q

Which structures allow the allow action potentials to penetrate or be transmitted, and spread to the interior of the muscle fiber?

A

Transverse tubules (T tubules)

**located at the A-I band junctions in mammalian heart muscle; located at z disks in frog muscle

58
Q

The overall process wherein the T tubule action potential cause release of calcium ions inside the muscle fiber in the immediate vicinity of the myofibrils, and these calcium ions then cause contraction.

A

Excitation-contraction coupling

59
Q

What is contained in the lumen of the T tubules?

A

extracellular fluid

**where the T tubules originate from the cell membrane, they are open to the exterior of the muscle fiber. Therefore, they communicate with the extracellular fluid surrounding the muscle fiber and contain extracellular fluid in their lumens.

60
Q

These structures are internal extensions of the cell membrane (sarcolemma)

A

T tubules

61
Q

What are the major parts of the sarcoplasmic reticulum?

A

Two terminal cisternae that abut the T tubules and

Long longitudinal tubules that surround all surfaces of the contracting myofibrils

62
Q

What receptors found in the T tubules sense voltage change caused by an action potential?

A

Dihydropyridine receptors (DHPR)

63
Q

Activation of DHPR triggers the opening of which channels of the terminal cisternae and longitudinal tubules of the SR?

A

Ryanodine receptors (RyR)

** these are calcium release channels linked to the DHPR of the T tubules

64
Q

This is the pump located in the walls of the SR that moves calcium ions away from the myofibrils back into the SR

A

SERCA

Sarcoplasmic Reticulum Ca2+-ATPase (can concentrate ions about 10,000-fold inside the tubules)

65
Q

This is the protein located inside the SR that binds calcium ions limiting the Ca++ concentration in the myofibrillar fluid

A

calsequestrin

66
Q

How many calcium ions can one molecule of calsequestrin bind?

A

4 calcium ions

67
Q

What is the normal resting state concentration of calcium ions in the cytosol that is too little to elicit contraction?

A

less than 10^-7 molar

68
Q

Full excitation of the T tubule and SR system causes release of calcium ions to increase the concentration in the myofibrillar fluid to as high as __________ molar concentration

A

2 x 10^-4 molar concentration

** this is a 500-fold increase, which is bout 20 times the level required to cause maximum muscle contraction.

69
Q

What is the total duration of the calcium pulse in the skeletal and cardiac muscle fiber respectively?

A

1/20 of a second in a skeletal muscle fiber

1/3 of a second in a cardiac muscle fiber (due to the long duration of the cardiac action potential)

70
Q

Give 3 anesthetics that may result to malignant hyperthermia and hypermetabolic crisis due to mutations of DHPR and RYR genes causing increased susceptibility during anesthesia

A

halothane
isoflurane
succinylcholine

**It is known that these mutations cause unregulated passage of calcium from the sarcoplasmic reticulum into the intracellular spaces, which in turn causes the muscle fibers to contract excessively. These sustained muscled contractions greatly increase metabolic rate, generating large amounts of heat and causing cellular acidosis, as a well as depletion of energy stores.

71
Q

After the administration of succinylcholine, the patient HR increased to 190 bpm and manifested muscle rigidity and high fever. What emergency condition is the patient suffering from?

A

Malignant hyperthermia

72
Q

This is the rapid breakdown of skeletal muscle that can be an additional complication of malignant hyperthermia

A

Rhabdomyolysis

73
Q

Potassium levels are also expected to (increase/decrease) in malignant hyperthermia

A

increase

**a high potassium level occurs due to release of large amounts of potassium from damaged muscle cells

74
Q

Apart from rapid cooling as treatment, which drug, known to antagonize the RYR receptors thus inhibiting calcium ion release from the SR, may also be administered to attenuate the muscle contraction during malignant hyperthermia or hypermetabolic crisis?

A

Dantrolene