4 - K+ Channels

Question 1

Most voltage-dependent ion channels have a __________ structure.

Answer 1

Most voltage-dependent ion channels have a tetrameric structure.

• 4- fold (4-domains) symmetric structure each with 6 TMD’s linked together via a “linker”
• Domains have a fixed composition and cannot ‘mix’

Question 2

What is the structure of a K+ channel?

Answer 2

K+ channel genes usually encode only one 6TM domain, so four proteins assemble to form the ion channel

• results in diverse channel functions depending on which subunits assemble

Question 3

What are three sources of variability of K+ channel function?

Answer 3

• Subunits may come from different genes (heteromeric channels)
• Alternative splice
  
  • different proteins arising from the same genes
• Assembly with modifying subunits (‘accessory subunits’ ; ‘auxiliary’ subunits ; beta subunits)

Question 4

What are 3 ‘Single’ Action Potential Effects of K+ channels?

Answer 4

• Set resting membrane potential
  
  • influences which stimulus is needed for neuron to fire (sensitivity)
• Influence AP shape
  
  • broad AP controlled by K+ channel
• Repolarize/hyperpolarize membrane

Question 5

What is the subunit composition of voltage-gated K+ channels? (how many subunits, what arrangement?)

Answer 5

Four-fold (ie four domain) symmetric structure each with 6 membrane spanning regions

K+ channel genes usually encode only one 6TMD so four proteins assemble to form the ion channel = heteromeric channel = great diversity

Modifying subunits include: accessory subunits, auxiliary subunits, beta subunits

Question 6

Differences between voltage-gated K+ channels vs Voltage-gated Na+ or Ca++ channels (selectivity, subunit arrangement)

Answer 6

Voltage-gated Na+ and Ca++ channels have a tetrameric structure with 4 homologous domains (I, II, III, IV) each with 6 membrane spanning regions. The domains are linked together with a “linker”

These domains have a fixed composition

Question 7

What is the definition of a delayed rectifier? (why delayed? Why rectifier?)

Answer 7

• Delayed: channels have a delayed sigmoidal opening
  
  • because these channels have many ‘pre-open’ states to go through before opening (all subunits must be activated for pore to open)
• Rectifier: K+ channels preferentially conduct ions OUT of the cell
  
  • 2 reasons:
    
    • intrinsic voltage dependence Their activity depends on voltage -
      
      • at neg voltages = mostly closed = low conductance
    • concentration gradient
      
      • K+ ions have a much higher concentration inside the cell relative to outside so at all physiological voltages, K+ ions tend to move out of the cell

Question 8

• Rectifier: K+ channels preferentially conduct ions OUT of the cell
  
  • 2 reasons:

Answer 8

• Rectifier: K+ channels preferentially conduct ions OUT of the cell
  
  • 2 reasons:
    
    • Their activity depends on voltage -
      
      • at neg voltages = mostly closed = low conductance
    • Concentration gradient: K+ ions have a much higher concentration inside the cell relative to outside so at all physiological voltages, K+ ions tend to move out of the cell

Question 9

What is a conductance-voltage relationship? What does it describe?

Answer 9

describes the conductance of a channel dependent of various voltages

Question 10

What controls activity of M- channels?

closed by?

activated by?

Answer 10

M-channels are closed by the muscarinic action of acetylcholine (ACh)

M-channels are activated (slowly) by depolarization

Question 11

What does closure of M-channel cause?

Answer 11

depolarization and suppression of the mechanism which limits repetitive discharge

• ACh is strongly excitatory in the CNS
  
  • depolarization
  • Enhanced repetitive discharge
  • Increased excitability

Question 12

M-channels require _____ to active

Answer 12

M-channels require PIP2 to active – cleaving pip2 shuts down the channel

ACh binding to M-channel cleaves PIP2

Question 13

_______ is a first-in-class potassium channel opener

Non-selective activator of neuronal ______ channels

Answer 13

Retigabine is a first-in-class potassium channel opener

Non-selective activator of neuronal KCNQ(2-5) (encode M-channels in NS) channels

Question 14

What happens to RMP when M-channels are inhibited by ACh? How does this effect AP?

Answer 14

RMP is higher because M-channels typically contribute to RMP

Neuron is hyperexcitable = bursting pattern (repetitive firing)

Question 15

What controls activity of BK channels? What underlies Ca++ sensitivity?

Answer 15

BK channels depend on both depolarization and internal [Ca++]

Ca++ sensing mechanism is intrinsic to the channel (encoded by channel gene) ie intracellular Ca++ sensing domain

Question 16

What controls the activity of SK channels? What underlies Ca++ sensitivity?

Answer 16

SK channels are Ca++ sensitive K+ channels

• Weakly voltage dependent
• Strongly Ca++ dependent
• Calcium sensitivity due to association with calmodulin (not encoded by the channel gene)

Question 17

Ca++ sensitivity of SK channels is due to:

Answer 17

Intracellular binding of Calmodulin - calmodulin senses Ca++

Question 18

SK channels are important for which phase of the action potential?

Answer 18

After hyperpolarization phase

AHP - effects further AP firing

Question 19

In absence of Ca++ what happens to the AHP?

Answer 19

After hyperpolarization phase

Absence of Ca++ = loss of AHP

Question 20

I_AHP (SK) channels generate _______ action potentials

Answer 20

I_AHP (SK) channels generate slow afterhyperpolarization of action potentials

= reduces excitability and eventually prevents firing

Question 21

I_AHP (SK) channels are blocked by ________

Answer 21

I_AHP (SK) channels are blocked by apamin

Question 22

What is spike frequency adaptation?

Answer 22

Activation of specific Ca++ activated potassium channels (SK (I_AHP)) results in termination of a burst of action potentials

Question 23

How is K,Ca channel (Ca++ activated K+ channel eg I_AHP (SK)) altered during repeated AP’s?

Answer 23

Influx of Ca++ leads to activation of K+ conductance that reduces excitability and eventually prevents firing = Spike frequency adaptation

Activation of Ca++ activated K+ channels results in termination of a burst of AP’s

Question 24

I_AHP can be responsible for ________ (terminate bursts) - generate rhythmic activity in neurons

Answer 24

I_AHP can be responsible for bursting pacemakers (terminate bursts) - generate rhythmic activity in neurons

At negative voltages an excitatory current is activated leading to subsequent burst

Question 25

What are two hallmark features of I,A?

Answer 25

A-currents = transient currents * N-type inactivation * ball and chain peptide at N-terminus - inactivates channel * I,A activated by depolarization but **exhibits rapid inactivation** * inactivated at normal resting potentials (~ -60mV)

Question 26

I_A is activated by ________ but to activate one must first remove inactivation by _______ cell

Answer 26

I_A is activated by _depolarization_ but to activate one must first remove inactivation by _hyperpolarizing_ cell

Question 27

I_A is blocked by ________ and \_\_\_\_\_\_\_\_\_

Answer 27

I_A is blocked by _4-aminopyridine (4-AP)_ and _dendrotoxin_

Question 28

How does stimulus intensity affect whether I_A can be activated?

Answer 28

With a weak input, membrane repolarization (AHP) is prominent and allows I_A to recover from inactivation With a strong input, I_A cannot recover (voltage doesn't reach sufficiently negative level) so AP's fire more readily

Question 29

What controls the activity of inward rectifier channels?

Answer 29

Inward rectifiers are voltage dependent but are not equipped with a voltage sensing domain therefore they have a natural blocking mechanism in which 4 pos charges enter the pore during depolarization and block the pore At Neg voltages these are pushed out

Question 30

Key functions of inward rectifier K+ channels?

Answer 30

* Strong contributor to RMP * Still allow action potentials to fire due to rapid inhibition during depolarization * Especially important in the plateau phase of the cardiac AP - Inhibition of K_IR channels allow Ca++ channel activity to maintain a depolarized membrane voltage