NESC 2570 Lecture Notes - Lecture 5: Hyperkalemic Periodic Paralysis, Channelopathy, Hyperkalemia
27 Jun 2018
School
Department
Course
Professor
Topology of the principal subunits of voltage gated Na+, Ca+, K+ and Cl-Channels
General structure
Alpha Subunit
N terminus (amino acids) and reaches the alpha helix and will go in the membrane spanning alpha helical
association. It ends at the c terminus on the cytoplasmic side
Motif 1 has 6 alphahelical regions
○
There are four motifs and therefore 24 alphahelicies
○
○
One of them is yellow, it is the fourth one of every motif (S4 - Segment 4) which is the part of theprotien that
senses the changes in the membrane potential and is thus responsible for making the channel open when it
depolarizes
○
The amino acid that goes in between segment 5 and 6
Part of it hangs into the membrane which is called the P-Loop (P stands for pore)
○
○
○
The two bata subunits
○
○
Almost the exact same as the image above - it is a voltage gated calcium channel
○
Same overall structure - N terminus, SI, S2, S3, S4 in yellow, C terminus on cytoplasm side, etc.
○
In this example, the bata subunit is different
○
○
This is a voltage gated potassium channel
○
Kv and HERG:
Crosses 6 times only once, there is only one of these subunits
This is the alpha subunit - because it is the largest subunit
○
○
Surprise Quiz question: For a fully functional voltage gated potassium channel, how many membrane spanning
alpha helical regions must there be?
24 - awweee you is kind. You is smart. You is important. You go Glen Coco
○
○
Calcium binding domain - binds calcium and changes susceptibility to opening channels
Calcium binds on the inside and changes its properties
○
○
○
Inward rectifier
It is not voltage gated because it doesn't have an S4
○
only a strong hyperpolarization can make it from being unblocked from potassium
○
Simplicity of K channel's gave rise to humans knowing anything about channel's at all
○
○
2-P channel
They're like two inward rectifiers stuck together
○
○
There is a lot of diversity n potassium channels
○
Voltage gate chloride channels are a big deal in muscle cells, not so much in neurons
○
All cells have 12 trans membrane alpha helix
○
A Charged Voltage Sensor Permits Voltage Dependent Gating of Ion Channels
P loop makes the pore which allows the ions to go through - it selects the different kinds of ions that it will let through
○
They are very specific an only allow potassium to go through - selectivity filter
○
Inner vestibule is the water filled cavity - whatever solution that is floating around inside the cell can go all the way up
○
S4 is loaded with positively charged side chain
○
Net positive charge ( all the plus's)
○
The protein is moved and it changes the conformation of the protein to open up the pore and an ion can move into the
channel
○
Gating current - is a tiny curent that flows across a membrane just at the moment where the channel "clicks"
○
This gating current is the current that flows the moment the channel opens
If a charge moves- that is called a current
○
○
Structure of a Simple Bacterial K+ Channel Determined by Crystallography
Proteins are hydrophobic so you could not use x- ray crystallography until antibodies were put on
○
McKinnon****
○
Two ions can be in the channel at once
○
Structural Features of K+Channel Gating
Newer model
○
Structure of a Mammalian Voltage Gated K+
Examples of Active Transporters
ATPase pump that uses the energy of ATP to move sodium in and potassium out
This is responsible for the sodium potassium exchange - pumps sodium in and potassium out
○
○
Pump calcium out
There are also ion moving proteins called ion exchangers
It exchanges sodium for calcium
○
○
There is one that accompanies metabolism and pumps one proton our while sodium comes in
○
No pump - it is just an exchange of an ion for an ion
○
○
These are co-transporters
○
They can use the sodium gradient to take up neurotransmitters such as GABA and Dopamine
○
People get introduced to the idea that chloride is an ion that will always hyperpolarize the cell - in general this is pretty much
the case but in adult neurons the intracellular chloride concentration will relatively depolarize the cell
○
NKCC makes chloride have an equilibrium potential for about -20mV, if you put in a neurotransmitter it would depolarize
E)
KKC2 makes a very negative chloride equilibrium potential (around -60mV)
F)
Ion Movements due to the Na+/K+Pump
Sodium will want to bind to these three sites
○
ATP comes along and the pump is phosphorylated and changes its structure and expose the sodium binding sites and lowers
its affinity
○
Affinity to binding potassium is high.
○
It changes the exposure and binding to both sodium and potassium such that sodium and potassium ions can move against
their gradient
○
Molecular Properties of the Na+/ K+Pump
Ouabain is a drug that will stop ATPase and stop their function -
○
C is the more complicated model
○
Toxins that Poison Ion Channels
Sodium channel toxins - can be released by scorpions and attacks the sodium potassium pump
It is moved to more negative potentials - there is always going to be open sodium channels which means it will
constantly depolarize and will remove inactivation
○
If that cell is a spiking cell, a huge elongation of an action potential happens and will paralyze the animal
○
The channels stay open and the activation of the voltage range goes to a more negative value
○
When a cell is depolarized, that means that the action potential will never end
○
Good example of what toxins do to channels
○
○
Cell attached patching - you will never get a single channel
When the sodium channel opens, it will not be able to shut all the way
○
○
Diseases Caused by Altered Ion Channels
A list of a couple human diseases that are associated with calcium channelopathies
Where the symbols are, is where the mutation is of each disease
○
FHM - weakens your muscles on one side of your body
○
CSNB (Congenital stationary night blindness) - night blindness, rod photoreceptors don't work right. You are born
with this disease and it is stationary so it does not get worse. It releases neurotransmitter in photoreceptors, so rods
cannot release glutamate
○
Paralysis - inhibits some movement
○
○
Generalized epilosy febrial sesuirez - goes away as it gets older, but it causes a baby to have seisures
○
Myotonia - rigidly paralyzed due to sodium channels remaining open
○
Paralysis - where the channels can't open
○
Episodic atatsia -
○
BFNC - mutated in the person's genome that leads to convulsions
○
Myotonia - rigid paralysis
○
Decay of the sodium current is slow, so they don't inactivate correctly
○
Sodium Channelopathy - Hyperkalemic Periodic Paralysis
Single sodium channel openings
○
Normal and mutant (hyperkalemic period paralysis)
○
Disease found in horses but not common in humans
○
Hyperkalemic - kalemia means potassium
Hyperkalemia is elevated potassium levels in the blood
○
This is important in horses because when people breed, they breed for it
Although it makes the horse strong, the muscle fibres will become rigid if the potassium levels are too high.
This will result in seizures
○
○
○
○
Channelopathies - Toxins and Mutations
October+5,+2015
2:30+PM
Topology of the principal subunits of voltage gated Na+, Ca+, K+ and Cl-Channels
General structure
Alpha Subunit
N terminus (amino acids) and reaches the alpha helix and will go in the membrane spanning alpha helical
association. It ends at the c terminus on the cytoplasmic side
Motif 1 has 6 alphahelical regions
○
There are four motifs and therefore 24 alphahelicies
○
○
One of them is yellow, it is the fourth one of every motif (S4 - Segment 4) which is the part of theprotien that
senses the changes in the membrane potential and is thus responsible for making the channel open when it
depolarizes
○
The amino acid that goes in between segment 5 and 6
Part of it hangs into the membrane which is called the P-Loop (P stands for pore)
○
○
○
The two bata subunits
○
○
Almost the exact same as the image above - it is a voltage gated calcium channel
○
Same overall structure - N terminus, SI, S2, S3, S4 in yellow, C terminus on cytoplasm side, etc.
○
In this example, the bata subunit is different
○
○
This is a voltage gated potassium channel
○
Kv and HERG:
Crosses 6 times only once, there is only one of these subunits
This is the alpha subunit - because it is the largest subunit
○
○
Surprise Quiz question: For a fully functional voltage gated potassium channel, how many membrane spanning
alpha helical regions must there be?
24 - awweee you is kind. You is smart. You is important. You go Glen Coco
○
○
Calcium binding domain - binds calcium and changes susceptibility to opening channels
Calcium binds on the inside and changes its properties
○
○
○
Inward rectifier
It is not voltage gated because it doesn't have an S4
○
only a strong hyperpolarization can make it from being unblocked from potassium
○
Simplicity of K channel's gave rise to humans knowing anything about channel's at all
○
○
2-P channel
They're like two inward rectifiers stuck together
○
○
There is a lot of diversity n potassium channels
○
Voltage gate chloride channels are a big deal in muscle cells, not so much in neurons
○
All cells have 12 trans membrane alpha helix
○
A Charged Voltage Sensor Permits Voltage Dependent Gating of Ion Channels
P loop makes the pore which allows the ions to go through - it selects the different kinds of ions that it will let through
○
They are very specific an only allow potassium to go through - selectivity filter
○
Inner vestibule is the water filled cavity - whatever solution that is floating around inside the cell can go all the way up
○
S4 is loaded with positively charged side chain
○
Net positive charge ( all the plus's)
○
The protein is moved and it changes the conformation of the protein to open up the pore and an ion can move into the
channel
○
Gating current - is a tiny curent that flows across a membrane just at the moment where the channel "clicks"
○
This gating current is the current that flows the moment the channel opens
If a charge moves- that is called a current
○
○
Structure of a Simple Bacterial K+ Channel Determined by Crystallography
Proteins are hydrophobic so you could not use x- ray crystallography until antibodies were put on
○
McKinnon****
○
Two ions can be in the channel at once
○
Structural Features of K+Channel Gating
Newer model
○
Structure of a Mammalian Voltage Gated K+
Examples of Active Transporters
ATPase pump that uses the energy of ATP to move sodium in and potassium out
This is responsible for the sodium potassium exchange - pumps sodium in and potassium out
○
○
Pump calcium out
There are also ion moving proteins called ion exchangers
It exchanges sodium for calcium
○
○
There is one that accompanies metabolism and pumps one proton our while sodium comes in
○
No pump - it is just an exchange of an ion for an ion
○
○
These are co-transporters
○
They can use the sodium gradient to take up neurotransmitters such as GABA and Dopamine
○
People get introduced to the idea that chloride is an ion that will always hyperpolarize the cell - in general this is pretty much
the case but in adult neurons the intracellular chloride concentration will relatively depolarize the cell
○
NKCC makes chloride have an equilibrium potential for about -20mV, if you put in a neurotransmitter it would depolarize
E)
KKC2 makes a very negative chloride equilibrium potential (around -60mV)
F)
Ion Movements due to the Na+/K+Pump
Sodium will want to bind to these three sites
○
ATP comes along and the pump is phosphorylated and changes its structure and expose the sodium binding sites and lowers
its affinity
○
Affinity to binding potassium is high.
○
It changes the exposure and binding to both sodium and potassium such that sodium and potassium ions can move against
their gradient
○
Molecular Properties of the Na+/ K+Pump
Ouabain is a drug that will stop ATPase and stop their function -
○
C is the more complicated model
○
Toxins that Poison Ion Channels
Sodium channel toxins - can be released by scorpions and attacks the sodium potassium pump
It is moved to more negative potentials - there is always going to be open sodium channels which means it will
constantly depolarize and will remove inactivation
○
If that cell is a spiking cell, a huge elongation of an action potential happens and will paralyze the animal
○
The channels stay open and the activation of the voltage range goes to a more negative value
○
When a cell is depolarized, that means that the action potential will never end
○
Good example of what toxins do to channels
○
○
Cell attached patching - you will never get a single channel
When the sodium channel opens, it will not be able to shut all the way
○
○
Diseases Caused by Altered Ion Channels
A list of a couple human diseases that are associated with calcium channelopathies
Where the symbols are, is where the mutation is of each disease
○
FHM - weakens your muscles on one side of your body
○
CSNB (Congenital stationary night blindness) - night blindness, rod photoreceptors don't work right. You are born
with this disease and it is stationary so it does not get worse. It releases neurotransmitter in photoreceptors, so rods
cannot release glutamate
○
Paralysis - inhibits some movement
○
○
Generalized epilosy febrial sesuirez - goes away as it gets older, but it causes a baby to have seisures
○
Myotonia - rigidly paralyzed due to sodium channels remaining open
○
Paralysis - where the channels can't open
○
Episodic atatsia -
○
BFNC - mutated in the person's genome that leads to convulsions
○
Myotonia - rigid paralysis
○
Decay of the sodium current is slow, so they don't inactivate correctly
○
Sodium Channelopathy - Hyperkalemic Periodic Paralysis
Single sodium channel openings
○
Normal and mutant (hyperkalemic period paralysis)
○
Disease found in horses but not common in humans
○
Hyperkalemic - kalemia means potassium
Hyperkalemia is elevated potassium levels in the blood
○
This is important in horses because when people breed, they breed for it
Although it makes the horse strong, the muscle fibres will become rigid if the potassium levels are too high.
This will result in seizures
○
○
○
○
Channelopathies - Toxins and Mutations
October+5,+2015
2:30+PM
Topology of the principal subunits of voltage gated Na+, Ca+, K+ and Cl-Channels
General structure
Alpha Subunit
N terminus (amino acids) and reaches the alpha helix and will go in the membrane spanning alpha helical
association. It ends at the c terminus on the cytoplasmic side
Motif 1 has 6 alphahelical regions
○
There are four motifs and therefore 24 alphahelicies
○
○
One of them is yellow, it is the fourth one of every motif (S4 - Segment 4) which is the part of theprotien that
senses the changes in the membrane potential and is thus responsible for making the channel open when it
depolarizes
○
The amino acid that goes in between segment 5 and 6
Part of it hangs into the membrane which is called the P-Loop (P stands for pore)
○
○
○
The two bata subunits
○
○
Almost the exact same as the image above - it is a voltage gated calcium channel
○
Same overall structure - N terminus, SI, S2, S3, S4 in yellow, C terminus on cytoplasm side, etc.
○
In this example, the bata subunit is different
○
○
This is a voltage gated potassium channel
○
Kv and HERG:
Crosses 6 times only once, there is only one of these subunits
This is the alpha subunit - because it is the largest subunit
○
○
Surprise Quiz question: For a fully functional voltage gated potassium channel, how many membrane spanning
alpha helical regions must there be?
24 - awweee you is kind. You is smart. You is important. You go Glen Coco
○
○
Calcium binding domain - binds calcium and changes susceptibility to opening channels
Calcium binds on the inside and changes its properties
○
○
○
Inward rectifier
It is not voltage gated because it doesn't have an S4
○
only a strong hyperpolarization can make it from being unblocked from potassium
○
Simplicity of K channel's gave rise to humans knowing anything about channel's at all
○
○
2-P channel
They're like two inward rectifiers stuck together
○
○
There is a lot of diversity n potassium channels
○
Voltage gate chloride channels are a big deal in muscle cells, not so much in neurons
○
All cells have 12 trans membrane alpha helix
○
A Charged Voltage Sensor Permits Voltage Dependent Gating of Ion Channels
P loop makes the pore which allows the ions to go through - it selects the different kinds of ions that it will let through
○
They are very specific an only allow potassium to go through - selectivity filter
○
Inner vestibule is the water filled cavity - whatever solution that is floating around inside the cell can go all the way up
○
S4 is loaded with positively charged side chain
○
Net positive charge ( all the plus's)
○
The protein is moved and it changes the conformation of the protein to open up the pore and an ion can move into the
channel
○
Gating current - is a tiny curent that flows across a membrane just at the moment where the channel "clicks"
○
This gating current is the current that flows the moment the channel opens
If a charge moves- that is called a current
○
○
Structure of a Simple Bacterial K+ Channel Determined by Crystallography
Proteins are hydrophobic so you could not use x- ray crystallography until antibodies were put on
○
McKinnon****
○
Two ions can be in the channel at once
○
Structural Features of K+Channel Gating
Newer model
○
Structure of a Mammalian Voltage Gated K+
Examples of Active Transporters
ATPase pump that uses the energy of ATP to move sodium in and potassium out
This is responsible for the sodium potassium exchange - pumps sodium in and potassium out
○
○
Pump calcium out
There are also ion moving proteins called ion exchangers
It exchanges sodium for calcium
○
○
There is one that accompanies metabolism and pumps one proton our while sodium comes in
○
No pump - it is just an exchange of an ion for an ion
○
○
These are co-transporters
○
They can use the sodium gradient to take up neurotransmitters such as GABA and Dopamine
○
People get introduced to the idea that chloride is an ion that will always hyperpolarize the cell - in general this is pretty much
the case but in adult neurons the intracellular chloride concentration will relatively depolarize the cell
○
NKCC makes chloride have an equilibrium potential for about -20mV, if you put in a neurotransmitter it would depolarize
E)
KKC2 makes a very negative chloride equilibrium potential (around -60mV)
F)
Ion Movements due to the Na+/K+Pump
Sodium will want to bind to these three sites
○
ATP comes along and the pump is phosphorylated and changes its structure and expose the sodium binding sites and lowers
its affinity
○
Affinity to binding potassium is high.
○
It changes the exposure and binding to both sodium and potassium such that sodium and potassium ions can move against
their gradient
○
Molecular Properties of the Na+/ K+Pump
Ouabain is a drug that will stop ATPase and stop their function -
○
C is the more complicated model
○
Toxins that Poison Ion Channels
Sodium channel toxins - can be released by scorpions and attacks the sodium potassium pump
It is moved to more negative potentials - there is always going to be open sodium channels which means it will
constantly depolarize and will remove inactivation
○
If that cell is a spiking cell, a huge elongation of an action potential happens and will paralyze the animal
○
The channels stay open and the activation of the voltage range goes to a more negative value
○
When a cell is depolarized, that means that the action potential will never end
○
Good example of what toxins do to channels
○
○
Cell attached patching - you will never get a single channel
When the sodium channel opens, it will not be able to shut all the way
○
○
Diseases Caused by Altered Ion Channels
A list of a couple human diseases that are associated with calcium channelopathies
Where the symbols are, is where the mutation is of each disease
○
FHM - weakens your muscles on one side of your body
○
CSNB (Congenital stationary night blindness) - night blindness, rod photoreceptors don't work right. You are born
with this disease and it is stationary so it does not get worse. It releases neurotransmitter in photoreceptors, so rods
cannot release glutamate
○
Paralysis - inhibits some movement
○
○
Generalized epilosy febrial sesuirez - goes away as it gets older, but it causes a baby to have seisures
○
Myotonia - rigidly paralyzed due to sodium channels remaining open
○
Paralysis - where the channels can't open
○
Episodic atatsia -
○
BFNC - mutated in the person's genome that leads to convulsions
○
Myotonia - rigid paralysis
○
Decay of the sodium current is slow, so they don't inactivate correctly
○
Sodium Channelopathy - Hyperkalemic Periodic Paralysis
Single sodium channel openings
○
Normal and mutant (hyperkalemic period paralysis)
○
Disease found in horses but not common in humans
○
Hyperkalemic - kalemia means potassium
Hyperkalemia is elevated potassium levels in the blood
○
This is important in horses because when people breed, they breed for it
Although it makes the horse strong, the muscle fibres will become rigid if the potassium levels are too high.
This will result in seizures
○
○
○
○
Channelopathies - Toxins and Mutations
October+5,+2015
2:30+PM
Document Summary
Topology of the principal subunits of voltage gated na+, ca+, k+ and cl- channels. N terminus (amino acids) and reaches the alpha helix and will go in the membrane spanning alpha helical association. It ends at the c terminus on the cytoplasmic side. There are four motifs and therefore 24 alphahelicies. The amino acid that goes in between segment 5 and 6. Part of it hangs into the membrane which is called the p-loop (p stands for pore) Almost the exact same as the image above - it is a voltage gated calcium channel. Same overall structure - n terminus, si, s2, s3, s4 in yellow, c terminus on cytoplasm side, etc. In this example, the bata subunit is different. Crosses 6 times only once, there is only one of these subunits. This is the alpha subunit - because it is the largest subunit. Calcium binding domain - binds calcium and changes susceptibility to opening channels.
