Potassium Channels

Question 1

Name the four families of potassium channels.

Answer 1

Voltage-gated (Kv).
Calcium-activated (Kca).
Inwardly-rectifying (Kir).
Two-pore (K2P).

Question 2

What are the four similarities between all four families of potassium channels?

Answer 2

Highly conserved selectivity filter within the pore.
Same tetrameric architecture with a single pore.
Enable potassium ions to flow across membrane.
Essential in controlling neuronal excitability.

Question 3

Describe the structure of inwardly-rectifying potassium channels (Kir).

Answer 3

Each subunit is formed of two transmembrane domains separated by a pore-forming region.
Subunits form tetramers to produce functional Kir channels.

Question 4

Kir channels show strong inward rectification. What does this mean?

Answer 4

Potassium ions move more easily into the cell than out.

Question 5

When are Kir channels activated and inactivated?

Answer 5

Activated around the equilibrium concentration for potassium (Ek), so helps to set and maintain the RMP.
Inactivated when membrane is depolarised to avoid opposing membrane excitation.

Question 6

Describe the structure of two-pore potassium channels.

Answer 6

Four transmembrane domains.
Two pore domains per subunit.
Functional channel is thought to consist of a dimer.

Question 7

What type of conductance do two-pore potassium channels contribute to?

Answer 7

“Leak” potassium conductance.

Question 8

Name six stimuli that regulate two-pore potassium channels.

Answer 8

pH.
O2 partial pressure.
Membrane stretch.
Temperature.
G-proteins.
Fatty acids.

Question 9

Describe the structure of calcium-activated potassium channels.

Answer 9

Share a similar structure to voltage-gated potassium channels.
Possess an extra transmembrane domain, named S0, that is involved in regulation by beta subunits.

Question 10

What regulates calcium-activated potassium channels.

Answer 10

Voltage.
Intracellular calcium.

Question 11

Describe the structure of voltage-gated potassium channels (Kv).

Answer 11

Six transmembrane domains per subunit.
Voltage sensor on S4.
Four alpha subunits form the pore region.
Alpha subunits associate with auxiliary beta subunits.

Question 12

What is the role of Kv channels?

Answer 12

Repolarise membranes in neurons and muscle cells.
Control AP frequency and duration.

Question 13

Why is potassium forced out of a neuron when Kv channels are activated?

Answer 13

High concentration of potassium inside the neuron.
Large ionic driving forces acting on neuron.

Question 14

What is the role of Kv1.1 channels in the axon and terminal?

Answer 14

Regulate excitability, AP propagation and synaptic transmission.

Question 15

What is the role of Kv4.3 channels in dendrites?

Answer 15

Constrain back-propagating APs in the dendritic tree.

Question 16

What is the role of Kv7.2/7.3 channels in the neuron?

Answer 16

Dampen excitability and repetitive firing.

Question 17

What is the role of Kca1.1 channels in the neuron?

Answer 17

Terminate the AP and generate after-hyperpolarisations that close calcium channels to stop synaptic transmission.

Question 18

Kv channels consist primarily of four identical alpha subunits. What is the name for this structure?

Answer 18

Homotetramer.

Question 19

What constitutes the main voltage-sensing region in Kv channels?

Answer 19

5 conserved arginine residues on S4 that repeat every 3 amino acid sequences.

Question 20

Describe the sliding helix model of Kv gating.

Answer 20

Charged S4 segments move, in relation to the channel protein, across the membrane in a manner similar to a peg in a hole.

Question 21

Describe the paddle model of Kv gating.

Answer 21

The gating charge is carried by paddles, composed of an alpha-helical hairpin formed by S3 and S4, on the outside of the channel that pivot against the membrane like levers, directly causing channel activation.

Question 22

Describe the transporter-like model of Kv gating.

Answer 22

The charged residues on S4 do not translocate across the membrane.
Instead, they pivot along their longitudinal axis, transporting the gating charge from an extracellular to an intracellularly connected water crevice, and coupling to the opening and closing of the ion channel.

Question 23

What is the role of the selectivity filter?

Answer 23

Allows passage of potassium ions that have shed their hydration shell.

Question 24

What is the BC gate?

Answer 24

The bundle crossing of the M2/S6 helices.

Question 25

What is the role of the BC gate?

Answer 25

Forms a barrier for hydrated potassium ions.

Question 26

How is the selectivity filter highly conserved?

Answer 26

The P-loop that forms the channel’s selectivity filter contains the TVGYGD signature sequence.
There is a highly conserved glycine residue in the middle of the inner pore helix.

Question 27

Why can the selectivity process be thought of as a series of stereochemical checkpoints?

Answer 27

The main constituents of the filter are oxygen atoms from amino-acid residues Thr-Val-Gly-Tyr-Gly. Each checkpoint consists of four oxygen atoms that occupy the corners of a square.

Question 28

The narrow size of the pore is thought to do what?

Answer 28

Strip potassium ions of their hydration shell as they enter the channel.

Question 29

What do the oxygen atoms of the selectivity filter do to the dehydrated potassium ions?

Answer 29

Act as surrogate waters.

Question 30

How do we know that Kv channels inactivate?

Answer 30

Potassium flow through open Kv channels slows considerably a few milliseconds after activation despite continued depolarisation.

Question 31

Define N-type inactivation of Kv channels.

Answer 31

Plugging of the pore after opening the cytoplasmic activation gate.

Question 32

Define C-type inactivation of Kv channels.

Answer 32

Collapsing the selectivity filter gate.

Question 33

Describe the mechanism of action for N-type inactivation.

Answer 33

The inactivation gate is formed by the hydrophobic residues on the N-terminus of the alpha subunit. This hinds to the central cavity of the pore of Kv channels.

Question 34

Describe the mechanism of action for C-type inactivation.

Answer 34

A slow process, resulting from conformational changes in the selectivity filter in the pore domain causing it to collapse in on itself.

Question 35

What are the three roles of auxiliary beta subunits of Kv channels?

Answer 35

Influence Kv channel surface expression.
Regulate N-type inactivation.
Play a role in redox sensing.

Question 36

How does PIP2 affect N-type inactivation?

Answer 36

Prevents it.

Question 37

How does depleting PIP2 affect current conductance?

Answer 37

PIP2 allows the S4-S5 linker to move freely. Depleting PIP2 shifts the voltage-dependence of activation and reduces the open probability of Kv channels, resulting in an overall decrease in the amount of current conducted.

Question 38

What gives rise to dynamic and reversible changes in Kv structure and function?

Answer 38

Posttranslational modification via cycles of phosphorylation and dephosphorylation by a wide variety of protein kinases and protein phosphatases.

Question 39

How do most toxins from animal venoms affect Kv channel function?

Answer 39

They block the central pore to prevent potassium ion transport. They either bind to the outer pore or block deep within the inner pore.

Question 40

How do spider toxins affect Kv channel function?

Answer 40

They are hydrophobic and target the voltage sensor. They are gating-modifier toxins.

Question 41

Name four animals that produce toxins that affect Kv channel function.

Answer 41

Tarantula.
Scorpion.
Sea anemone.
Cone snail.

Question 42

How does activation of potassium channels affect excitability?

Answer 42

Reduces excitability.

Question 43

How does inhibition of potassium channels affect excitability?

Answer 43

Increase excitability.