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MCBM Part 2 > Wagner - Propagation of the Action Potential > Flashcards

Wagner - Propagation of the Action Potential Flashcards

1
Q

A net integration yielding a suprathreshold depolarization at the axon hillock results in

A

activation of voltage-gated Na+ channels and triggers an action potential

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2
Q

What activates additional voltage-gated Na+ channels to propagate the action potential further down the axon?

A

the depolarization of plasma membrane segment due to the initial Na+ influx depositing positive charge

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3
Q

What can you expect if the axial resistance (Ra) of the cytoplasm is high?

A

a slower conduction velocity

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4
Q

Increasing axon diameter decreases _____, but also increases ____and_____ which reduces membrane resistance (Rm).

A 
axoplasmic resistance (Ra)
surface area and membrane capacitance (Cm)
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5
Q

Why does a decrease in Ra due to an increase in axon diameter have a greater functional impact?

A

because Ra varies inversely with the square of the axon diameter

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6
Q

What is the overall benefit of increasing the axon diameter?

A

longitudinal current flow (λ) and conduction velocity (Vc) both increase

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7
Q

What can you expect with a high Cm?

A

a slower conduction velocity

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8
Q

How does myelination decrease capacitance (Cm)?

A

By increasing the separation between extracellular and cytoplasmic sides of plasma membrane

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9
Q

Since the myelin sheath increases the insulation of the plasma membrane thereby increasing Rm, what counteracts this?

A

The Nodes of Ranvier interrupt the myelin sheath every 1-2mm and have dense clusters of Na+ channels to ensure that depolarizing inward Na+ current is produced allowing replication of the action potential at each node down the length of the axon

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10
Q

What do myelin and the Nodes of Ranvier increase?

A

λ=longitudinal current flow and Vc=conduction velocity

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11
Q

The pattern by which an action potential jumps from node to node is known as…

A

Saltatory Conduction

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12
Q

What are 3 general things to know about voltage-gated NA+ channels?

A
  1. rapidly activated by depolarization
  2. subject to rapid inactivation
  3. TTX sensitive
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13
Q

The Na+ channels are composed of an α & β subunit expressed in what ratio?

A

1:1 stoichiometric ratio

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14
Q

Which subunit consists of 4 linked homologous repeats each containing 6 transmembrane domains (Na+ channel)?

A

the α subunit

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15
Q

Which subunit can influence or modulate the amplitude of current and the kinetics of activation in Na+ channel?

A

the regulatory β subunit which is a glycoprotein with a single transmembrane domain

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16
Q

The Na+ channel ion pore comprises what transmembrane segments?

A

S5 & S6 and the intervening extracellular loop

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17
Q

What is the cause of TTX sensitivity in Na+ channel’s α subunit (subtypes 1-3 in CNS)?

A

a Glutamate residue at the 387th position (E387) and a Tyrosine residue at the 385th position (Y385) in extracellular loop between S5 & S6 of repeat 1

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18
Q

Of the 8 α subtypes why are α subtypes(1-3) 200x more sensitive (Na+ channels)?

A

because the α subtypes 1-3 have a Tyrosine residue instead of a Cysteine residue at position 385

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19
Q

What interactions and critical residues are responsible for Na+ selectivity in α subunit of Na+ channels?

A

interactions between S5 & S6 and the intervening extracellular loop, residues K1422 of repeat III and A1712 of repeat IV

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20
Q

Na+ channel activation is regulated by what 2 residues that serve as voltage sensors?

A

Basic residues Arginine and Lysine at every 3rd position in S4 of α subunit enable it to exist as an amphipathic helix

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21
Q

How does S4 of the α subunit respond to local depolarization in Na channels?

A

With a clockwise rotational conformation change that externalizes two positive charges resulting in gating current before channel opening

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22
Q

How is channel inactivation regulated in α subunit of NA+ channels?

A

Regulated by the hydrophobic latch within linking repeats III & IV formed by Isoleucine, Phenylalanine, and Methionine at positions 1488-1490

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23
Q

How many subfamilies of depolarization-activated, voltage-gated K+ (Kv) channels are there and how many subtypes of α subunits do they have?

A

there are 4 subfamilies with each one having up to 9 different subtypes

24
Q

The α subunits of Kv contain 6 transmembrane proteins arranged as homotetramers and heterotetramers, but are not what?

A

They are NOT covalently linked together as four repeats

25
Q

Tetramer formation is dependent on what for Kv channels?

A

The T domain, a stretch of 114 amino acid residues

26
Q

Where is the T domain located in Kv channels?

A

within the N terminal region near the S1 segment

27
Q

What makes up the ion pore in Kv channels?

A

extracellular H5 loop linking S5 &S6 lines the pore, while interactions between S6 and cytoplasmic loop linking S4 & S5 form pore mouth

28
Q

In Kv channels what is K+ selectivity and TEA sensitivity due to?

A

consensus sequence (T/S)xxTxGYG located in H5 loop region

29
Q

True or False: Depolarization-dependent channel activation for Kv is the same as that of Na+ channels.

A

True! voltage-sensing amphipathic α helix within the S4 segment

30
Q

Kv channel inactivation varies greatly. Name the two types discussed in class and state which is the fast inactivation.

A

N-type = FAST inactivation and C-type inactivation

31
Q

How does the N-type inactivation work?

A

N-terminus or β subunit contain an “inactivation ball” that interacts with cytoplasmic loop between S4 & S5 and form an “inactivation gate”

Example: Kv 4 channels mediating A-type K+ current

32
Q

How does c-type inactivation work?

A

due to conformational changes at the C terminal domain

33
Q

True or False: All Kv channels inactivate.

A

False! Some channels do not inactivate at all!

Example: the delayed rectifier, involved in membrane repolarization during action potential

34
Q

List the 6 known subtypes of Ca 2+ channels and how they differ.

A

subtypes: T, L, N, P, Q &R
differ in: depolarization threshold of activation, rates of inactivation, and sensitivity to channels blockers and toxins

35
Q

With regard to activation and inactivation what do T-type Ca 2+ channels posses?

A

lowest activation threshold and highest rate of inactivation

36
Q

With regard to activation and inactivation what do L-type Ca 2+ channels posses?

A

highest activation threshold and lowest rate of inactivation

37
Q

What blocks the following channels:

  1. L-type
  2. N-type
  3. P & Q-type
A
  1. dihydropyridine drugs
  2. shellfish toxins (ω-conotoxins)
  3. spider toxins (ω-agatoxins)
38
Q

Voltage-gated Ca 2+ channels consist of 5 subunits, please list them.

A

α1, α2, β, γ & δ

39
Q

The α1 subunit of Ca 2+ channels is similar to that of Na+ α subunit in what manner?

A

it has 4 covalently linked repeats of 6 transmembrane domains, depolarization-activation sensor in S4, and an extracellular loop linking S5 & S6 which lines the pore and forms extracellular mouth of the pore

40
Q

What residues provide the high affinity for Ca 2+ binding and serve as selectivity filters?

A

Glutamate residues

41
Q

In Ca 2+ channels inactivation is regulated by 3 methods, please list them

A
  1. S6 segment on repeat 1
  2. cytoplasmic loop linking repeats I & II (G protein-dependent inactivation)
  3. C terminus (Ca 2+ dependent inactivation in L-type channels)
42
Q

Which subunit can serve as phosphorylation-dependent regulation site for Ca 2+ channels?

A

cytoplasmic β subunit

43
Q

What does SCN4A mean and what chromosome is it located on?

A

α-subunit gene on skeletal muscle, voltage-gated Na+ channel located on chromosome 17 (q23-25)

44
Q

20 mutations can cause 3 distinct & related disorders primarily localized to what 3 regions of the α subunit?

A

cytoplasmic side of S5 &S6 segments, inactivation loop, and the S4 segment

45
Q

What are the three disorders and how many mutations are known to cause each?

A

Hyperkalemic periodic paralysis (4 mutations)
Potassium-aggravated myotonia (6 mutations)
Paramyotonia congenita (9 mutations)

46
Q

What is potassium-aggravated myotonia characterized by?

A

muscular hyperexcitability due to mildly elevated extracellular potassium levels

47
Q

What can provoke Hyperkalemic periodic paralysis?

A

exercise, stress, and/or diet-induced hyperkalemia

48
Q

What are symptoms of Hyperkalemic periodic paralysis?

A

muscular weakness and paralysis, which may be preceded by myotonia or fasciculations

49
Q

Paramyotonia congenita is known to evoke what?

A

muscular excitability induced by cold and worsened by exercise

50
Q

The following symptoms are included in which disorder?

muscular rigidity and stiffness that may be followed by paralysis

A

Paramyotonia congenita

51
Q

In paramyotonia there is an exception that causes latent paralysis what is this exception?

A

T1313M causes delayed paralysis following cold-induced myotonia

52
Q

What 3 things do the mutations within the S4 segment in pramyotonia congenita cause?

A
  1. slowing of inactivation kinetics
  2. interference of cycling between activation & inactivation
  3. production of a small Na+ current and muscle cell depolarization toward action potential threshold
53
Q

Potassium-aggravated myotonia is due to mutations at residue 1306 that vary in severity. List the 3 mutations in order of severity from high to low.

A

glutamate > valine > alanine

54
Q

What do these mutations cause?

A
  1. marked slowing in inactivation kinetics
  2. persistent fractional Na+ current
  3. near threshold muscle cell depolarization
55
Q

What do mutations at residues 704, 1360, and 1592 in Hyperkalemic periodic paralysis compromise?

A

compromise the interaction between the S5/S6 segments and the inactivation loop and latch

56
Q

What does the compromise caused by Hyperkalemic periodic paralysis lead to?

A
  1. incomplete inactivation
  2. fractional, sustained Na+ current depolarizes muscle cells above threshold
  3. repolarization is not sufficient to reactivate channels
57
Q

What does channel inactivation for extended periods lead to?

A

Muscle cell paralysis of the affected muscle fiber

MCBM Part 2 (15 decks)

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