Wagner - Propagation of the Action Potential Flashcards
A net integration yielding a suprathreshold depolarization at the axon hillock results in
activation of voltage-gated Na+ channels and triggers an action potential
What activates additional voltage-gated Na+ channels to propagate the action potential further down the axon?
the depolarization of plasma membrane segment due to the initial Na+ influx depositing positive charge
What can you expect if the axial resistance (Ra) of the cytoplasm is high?
a slower conduction velocity
Increasing axon diameter decreases _____, but also increases ____and_____ which reduces membrane resistance (Rm).
axoplasmic resistance (Ra) surface area and membrane capacitance (Cm)
Why does a decrease in Ra due to an increase in axon diameter have a greater functional impact?
because Ra varies inversely with the square of the axon diameter
What is the overall benefit of increasing the axon diameter?
longitudinal current flow (λ) and conduction velocity (Vc) both increase
What can you expect with a high Cm?
a slower conduction velocity
How does myelination decrease capacitance (Cm)?
By increasing the separation between extracellular and cytoplasmic sides of plasma membrane
Since the myelin sheath increases the insulation of the plasma membrane thereby increasing Rm, what counteracts this?
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
What do myelin and the Nodes of Ranvier increase?
λ=longitudinal current flow and Vc=conduction velocity
The pattern by which an action potential jumps from node to node is known as…
Saltatory Conduction
What are 3 general things to know about voltage-gated NA+ channels?
- rapidly activated by depolarization
- subject to rapid inactivation
- TTX sensitive
The Na+ channels are composed of an α & β subunit expressed in what ratio?
1:1 stoichiometric ratio
Which subunit consists of 4 linked homologous repeats each containing 6 transmembrane domains (Na+ channel)?
the α subunit
Which subunit can influence or modulate the amplitude of current and the kinetics of activation in Na+ channel?
the regulatory β subunit which is a glycoprotein with a single transmembrane domain
The Na+ channel ion pore comprises what transmembrane segments?
S5 & S6 and the intervening extracellular loop
What is the cause of TTX sensitivity in Na+ channel’s α subunit (subtypes 1-3 in CNS)?
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
Of the 8 α subtypes why are α subtypes(1-3) 200x more sensitive (Na+ channels)?
because the α subtypes 1-3 have a Tyrosine residue instead of a Cysteine residue at position 385
What interactions and critical residues are responsible for Na+ selectivity in α subunit of Na+ channels?
interactions between S5 & S6 and the intervening extracellular loop, residues K1422 of repeat III and A1712 of repeat IV
Na+ channel activation is regulated by what 2 residues that serve as voltage sensors?
Basic residues Arginine and Lysine at every 3rd position in S4 of α subunit enable it to exist as an amphipathic helix
How does S4 of the α subunit respond to local depolarization in Na channels?
With a clockwise rotational conformation change that externalizes two positive charges resulting in gating current before channel opening
How is channel inactivation regulated in α subunit of NA+ channels?
Regulated by the hydrophobic latch within linking repeats III & IV formed by Isoleucine, Phenylalanine, and Methionine at positions 1488-1490
How many subfamilies of depolarization-activated, voltage-gated K+ (Kv) channels are there and how many subtypes of α subunits do they have?
there are 4 subfamilies with each one having up to 9 different subtypes
The α subunits of Kv contain 6 transmembrane proteins arranged as homotetramers and heterotetramers, but are not what?
They are NOT covalently linked together as four repeats
Tetramer formation is dependent on what for Kv channels?
The T domain, a stretch of 114 amino acid residues
Where is the T domain located in Kv channels?
within the N terminal region near the S1 segment
What makes up the ion pore in Kv channels?
extracellular H5 loop linking S5 &S6 lines the pore, while interactions between S6 and cytoplasmic loop linking S4 & S5 form pore mouth
In Kv channels what is K+ selectivity and TEA sensitivity due to?
consensus sequence (T/S)xxTxGYG located in H5 loop region
True or False: Depolarization-dependent channel activation for Kv is the same as that of Na+ channels.
True! voltage-sensing amphipathic α helix within the S4 segment
Kv channel inactivation varies greatly. Name the two types discussed in class and state which is the fast inactivation.
N-type = FAST inactivation and C-type inactivation
How does the N-type inactivation work?
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
How does c-type inactivation work?
due to conformational changes at the C terminal domain
True or False: All Kv channels inactivate.
False! Some channels do not inactivate at all!
Example: the delayed rectifier, involved in membrane repolarization during action potential
List the 6 known subtypes of Ca 2+ channels and how they differ.
subtypes: T, L, N, P, Q &R
differ in: depolarization threshold of activation, rates of inactivation, and sensitivity to channels blockers and toxins
With regard to activation and inactivation what do T-type Ca 2+ channels posses?
lowest activation threshold and highest rate of inactivation
With regard to activation and inactivation what do L-type Ca 2+ channels posses?
highest activation threshold and lowest rate of inactivation
What blocks the following channels:
- L-type
- N-type
- P & Q-type
- dihydropyridine drugs
- shellfish toxins (ω-conotoxins)
- spider toxins (ω-agatoxins)
Voltage-gated Ca 2+ channels consist of 5 subunits, please list them.
α1, α2, β, γ & δ
The α1 subunit of Ca 2+ channels is similar to that of Na+ α subunit in what manner?
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
What residues provide the high affinity for Ca 2+ binding and serve as selectivity filters?
Glutamate residues
In Ca 2+ channels inactivation is regulated by 3 methods, please list them
- S6 segment on repeat 1
- cytoplasmic loop linking repeats I & II (G protein-dependent inactivation)
- C terminus (Ca 2+ dependent inactivation in L-type channels)
Which subunit can serve as phosphorylation-dependent regulation site for Ca 2+ channels?
cytoplasmic β subunit
What does SCN4A mean and what chromosome is it located on?
α-subunit gene on skeletal muscle, voltage-gated Na+ channel located on chromosome 17 (q23-25)
20 mutations can cause 3 distinct & related disorders primarily localized to what 3 regions of the α subunit?
cytoplasmic side of S5 &S6 segments, inactivation loop, and the S4 segment
What are the three disorders and how many mutations are known to cause each?
Hyperkalemic periodic paralysis (4 mutations)
Potassium-aggravated myotonia (6 mutations)
Paramyotonia congenita (9 mutations)
What is potassium-aggravated myotonia characterized by?
muscular hyperexcitability due to mildly elevated extracellular potassium levels
What can provoke Hyperkalemic periodic paralysis?
exercise, stress, and/or diet-induced hyperkalemia
What are symptoms of Hyperkalemic periodic paralysis?
muscular weakness and paralysis, which may be preceded by myotonia or fasciculations
Paramyotonia congenita is known to evoke what?
muscular excitability induced by cold and worsened by exercise
The following symptoms are included in which disorder?
muscular rigidity and stiffness that may be followed by paralysis
Paramyotonia congenita
In paramyotonia there is an exception that causes latent paralysis what is this exception?
T1313M causes delayed paralysis following cold-induced myotonia
What 3 things do the mutations within the S4 segment in pramyotonia congenita cause?
- slowing of inactivation kinetics
- interference of cycling between activation & inactivation
- production of a small Na+ current and muscle cell depolarization toward action potential threshold
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.
glutamate > valine > alanine
What do these mutations cause?
- marked slowing in inactivation kinetics
- persistent fractional Na+ current
- near threshold muscle cell depolarization
What do mutations at residues 704, 1360, and 1592 in Hyperkalemic periodic paralysis compromise?
compromise the interaction between the S5/S6 segments and the inactivation loop and latch
What does the compromise caused by Hyperkalemic periodic paralysis lead to?
- incomplete inactivation
- fractional, sustained Na+ current depolarizes muscle cells above threshold
- repolarization is not sufficient to reactivate channels
What does channel inactivation for extended periods lead to?
Muscle cell paralysis of the affected muscle fiber
