Ion Channels Flashcards
1
Q
What types of channels are present in the somatodendritic portion of the neuron?
A
- The “somatodendritic” portion will have hyperpolarization activated nucleotide-gated channels (HCN) and voltage gated potassium channels (KV) that prevent backward excitatory propagation. This keeps dendrites from experiencing “unwanted” LTP/LTD
- By changing channels at the dendrite, in a dynamic way, the resting potential could be more hyperpolarized and this could regulate dendritic excitability
2
Q
What types of channels are present in the axon initial segment?
A
- The axon initial segment contains voltage gated sodium channels and voltage gated KCNQ channels. - The threshold of when these channels will open dictates what the action potential threshold is
- Thus, neurons that have different variants of these channels in the AIS will have different action potential threshold and be easier/harder to activate
3
Q
What types of channels are present in the nodes of Ranvier?
A
- The nodes of Ranvier contain various voltage gated sodium (NaV), KCNQ, and other voltage gated potassium channels (Kv)
4
Q
What types of channels are present in the axon terminal?
A
The axon terminal will have NaV, Kv, and of course the CaV channels you are familiar with
5
Q
Myelinating Cells Location and importance
A
- Adjacent to the nodes are the myelinating cells (Schwann or oligodendrocytes)
- Important for keeping node membrane proteins within the node
6
Q
The Paranodal Axoglial Junctions
A
- The paranodes are important as barriers to separate the nodes, where AP generation occurs, and the myelinated portions of the axon
- As such, the PNJ contains a high density of cytoskeletal and anchoring proteins, such as AnKB
- The PNJ is thought to cluster important proteins into lipid rafts during development, and studies show that mutations to PNJ proteins disrupts proper nodes of Ranvier formation
- In humans with a natural mutation to the protein Caspr (green, right), their nerve conduction velocity is significantly slower
7
Q
Juxtaparanodes
A
- Are adjacent to the paranodal regions, beneath myelin covered portions
- These areas contain certain isoforms of voltages gated potassium channels that are thought to maintain resting potential in this region
8
Q
Internodes
A
- Regions where axonal membrane typically has no ion channels or signaling components
- This is typically the area we refer to in NSCI classes as “being myelinated and not expressing any channels”
9
Q
How are Nodes of Ranvier established during development on the axon?
A
- AnkG clusters channels at the axon initial segment as well as the nodes
- Mutation experiments show that if AnkG expression is silenced, NaV channels no longer cluster together
- During development, the contact of the myelin cells to the axons, which forms the paranodal junction, is what allows the AnkG/Na/Kv cluster to occur at the nodes.
- Basically, the paranodes form first and then this boundary allows the nodes of Ranvier to establish themselves
10
Q
What are ion channels made up of?
A
Ion channels are generally made up of one contiguous amino acid chain, with multiple tertiary structures called domains
- The entirety of the ion channel would be the quaternary structure
- Channel domains are made up of smaller subunits, labeled S1-S6
11
Q
Voltage gated calcium and sodium channels structure
A
four domains that circle around to form a pore, with each domain having a voltage sensor
12
Q
Voltage gated potassium channels
A
have four separate domains that circle to form the pore
13
Q
WHat guides ion channels to specific areas?
A
- The voltage gated ion channels also interact with auxiliary units (a2, b, g, d) that are also located on the membrane. These interactions can help guide certain channels to the somatodendritic areas, such as HCN, Kv, and others to the axon
14
Q
WHat intracellular proteins anchor the channels to the cytoskeleton
A
- Voltage gated sodium channels, for example (right), will have AnkG binding to stabilize it to the microtubules and actin
- The channels will also have associated protein units that are also embedded into the membrane; contactin and NrCAM are just a few examples
15
Q
voltage gated channel sensors and 2 keys and response
A
- Voltage gated channels respond to changes in membrane potential. They have a string of amino acids, called the voltage sensor, in the pore region that responds to a change in voltage
- The key to voltage gated channels is charge. Positive charges are repelled by like charges, whereas opposite charges attract
- Depending on the potential of the intracellular environment, the voltage sensor can be attracted/repelled and cause the channel to open/close
- Most voltage-gated channels respond depolarization, meaning positive charge. However there are some channels that respond to hyperpolarization
16
Q
Where is the voltage sensor?
A
S4 helix
17
Q
S4 and the voltage sensor
A
- The S4 helix spans the lipid bilayer and when the membrane potential changes, it causes movement of the S4-S5 linker region, which in turn moves the S6 helix in the pore. The movement of the S6 region is what physically blocks/opens channel.
- Each of the four domains have the S4 voltage sensor, so in total each voltage gated channels has 4 voltage sensors
- The S4 region has many positively charged amino acids, which respond to the intracellular depolarization by “repelling.” This physically moves the S4-S6 regions
18
Q
How does the voltage sensor move?
A
- The voltage sensor (S4) is thought move in response to depolarization in a helical screw movement. The S4 region essentially rotates around and up in response to depolarization.
- Mutations in the ion channels is what helps determine channel movement
- The 4 voltage sensors on each unit move in a concerted way so that the S6 regions blocking the pore move together. The pore is then open and ions can flow.
- The lipid bilayer also plays a key role in channel function—the negatively charges phospholipid heads help stabilize the positive gating charges
19
Q
Why do channels not stay open indefinitely?
A
- Most voltage gated channels, including the key channels involved in actions potentials (Kv and Nav), inactivate even though the membrane potential remains depolarized
- Recall that in an action potential, both sodium and potassium channels close even thought the membrane is depolarized - There are two mechanisms for inactivation that voltage gated channels use: N-type inactivation and C-type inactivation
20
Q
N-type
A
- This type is also known as “ball and chain.”
- There is a group of amino acids as part of the channel structure located intracellularly (“the ball”). When the pore opens, this “ball” swings over and binds to a region within the pore, blocking ion movement
- When then membrane potential becomes hyperpolarized, the voltage sensor shifts back to the original position, which releases the inactivation “ball” from its binding site because the regions once exposed are no longer
- The channel is now closed due to the voltage sensor and the inactivation gate is reset
21
Q
C-type
A
- This type of inactivation is caused by movement of the pore regions of the channel
- The p-loop regions of the channel collapse and prevent ion movement
- When there are many ions, inactivation is prevented because the physical structure of the ions keeps the channel from collapsing
- When ion movement slows, the pore region collapses, causing inactivation
22
Q
What other factors determine channel opening?
A
- GPCRs can cause ion channels to open/close
- The g-protein subunits α-GDP/ βγ are at the GPCR. When a ligand binds the GPCR, the GDP is switched to s GTP on α, and the complex dissociates. The α subunit can act via Gq, Gi or Gs pathway depending on what the α unit is. The α units and βγ can directly or indirectly activate ion channels.
23
Q
The interaction with βγ or any of the intracellular signaling components of GPCR have specific effects on the ion channel
A
The basis for these effects is that binding of the ion channel by these second messengers changes the conformation in a way that facilitates or inhibits channel opening
24
Q
How do Channels have selectivity for the types of ions they allow through?
A
the size of the pore and the charges that lines the pore mediate this selectivity
25
potassium selectivity : rate
- We know there are multiple binding sites for potassium in Kv channels because of the rate of potassium movement in the channel. The rate at which potassium ions move out is higher than the driving force would suggest. This is because if 2 potassium ions bind in the pore, then the way out if blocked in one direction. Thus there is a greater flow in one direction
26
potassium selectivity : atomic radius
- The Kv potassium channel is selective for potassium over other cations due to the atomic radius of potassium.
- The channel is arranged so that only ions of a certain size can fully interact with the side groups lining the pore of the channel.
- Sodium has a smaller atomic radius and so cannot interact with the selectivity filter as efficiently
27
sodium ion permeability
- Sodium selectivity comes from the outer most binding site for sodium, which is more effective at binding sodium’s atomic radius than potassium. Thus, only sodium can pass through even though the pore might be large enough to handle potassium as well
28
calcium ion permeability
- If calcium concentration is low, sodium can occupy the calcium binding sites
- Because calcium binds the selectivity regions most efficiently, when calcium concentration is high enough, only calcium passes through the channel
- The atomic radius of calcium and sodium are much closer than calcium/potassium or sodium/potassium. This is why calcium/sodium cross-permeability can occur
29
regular, train firing
Regular, train firing as in cortical pyramidal cells. The stronger the depolarization the more action potentials that fire, one by one
30
rhythmic, burst firing
Rhythmic, burst firing, as with thalamic relay neurons. Action potentials cluster together.
31
short duration, high frequency
Short duration, high frequency firing, as in many GABA interneurons
32
low frequency
Low frequency produce action potentials, common with modulatory neurotransmitters
33
Three characteristics of ion current determine what type of firing a neuron will produce
- The type of ions that move through the ion channel
- The voltage and time dependence of that ion channel
- Sensitivity of the ion channel to second messengers
34
Types of sodium currents
- There is a sodium current that activates/inactivates during an action potential
- There is another type of sodium current that is prolonged, known as the persistent sodium current. This current enhances and facilitates depolarization because it makes the neuron more depolarized at rest—note the resting membrane potential is not changed, this is small current
- Function: enhance functional synaptic responses for learning tasks
35
types of potassium currents
- The standard voltage gated potassium current occurs during the peak of action potentials—the potassium channels open but do not inactivate
- There are voltage gated potassium channels that have inactivation properties, working similar to the N-type inactivation
- There are other voltage gated potassium channels that respond to calcium level or secondary signaling messengers
- Finally, there is a set of potassium channels that are even slower to close than the “typical” voltage gated potassium channels we discussed
A. The function of these channels is to regulate how cells respond to excitation-modulatory function
36
Types of calcium currents
- Calcium channels, like sodium and potassium channels, have differences in their response properties
- There are transient calcium channels, long-lasting calcium channels, and channels that do not fit neatly into either category
- A neuron will express multiple type of voltage gated calcium channels
- During an action potential, there is a subtype of calcium channel that activates, allowing in calcium, which then opens a specific calcium-gated potassium channel (the SK channel)—this occurs in purkinje cells in the cerebellum
