4 - K+ Channels Flashcards
Most voltage-dependent ion channels have a __________ structure.
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’
What is the structure of a K+ channel?
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
What are three sources of variability of K+ channel function?
- 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)
What are 3 ‘Single’ Action Potential Effects of K+ channels?
- 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
What is the subunit composition of voltage-gated K+ channels? (how many subunits, what arrangement?)
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
Differences between voltage-gated K+ channels vs Voltage-gated Na+ or Ca++ channels (selectivity, subunit arrangement)
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
What is the definition of a delayed rectifier? (why delayed? Why rectifier?)
- 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
-
intrinsic voltage dependence Their activity depends on voltage -
- 2 reasons:
- Rectifier: K+ channels preferentially conduct ions OUT of the cell
- 2 reasons:
- 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
- Their activity depends on voltage -
- 2 reasons:
What is a conductance-voltage relationship? What does it describe?
describes the conductance of a channel dependent of various voltages
What controls activity of M- channels?
closed by?
activated by?
M-channels are closed by the muscarinic action of acetylcholine (ACh)
M-channels are activated (slowly) by depolarization
What does closure of M-channel cause?
depolarization and suppression of the mechanism which limits repetitive discharge
- ACh is strongly excitatory in the CNS
- depolarization
- Enhanced repetitive discharge
- Increased excitability
M-channels require _____ to active
M-channels require PIP2 to active – cleaving pip2 shuts down the channel
ACh binding to M-channel cleaves PIP2
_______ is a first-in-class potassium channel opener
Non-selective activator of neuronal ______ channels
Retigabine is a first-in-class potassium channel opener
Non-selective activator of neuronal KCNQ(2-5) (encode M-channels in NS) channels
What happens to RMP when M-channels are inhibited by ACh? How does this effect AP?
RMP is higher because M-channels typically contribute to RMP
Neuron is hyperexcitable = bursting pattern (repetitive firing)
What controls activity of BK channels? What underlies Ca++ sensitivity?
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
What controls the activity of SK channels? What underlies Ca++ sensitivity?
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)
Ca++ sensitivity of SK channels is due to:
Intracellular binding of Calmodulin - calmodulin senses Ca++
SK channels are important for which phase of the action potential?
After hyperpolarization phase
AHP - effects further AP firing
In absence of Ca++ what happens to the AHP?
After hyperpolarization phase
Absence of Ca++ = loss of AHP
IAHP (SK) channels generate _______ action potentials
IAHP (SK) channels generate slow afterhyperpolarization of action potentials
= reduces excitability and eventually prevents firing
IAHP (SK) channels are blocked by ________
IAHP (SK) channels are blocked by apamin
What is spike frequency adaptation?
Activation of specific Ca++ activated potassium channels (SK (IAHP)) results in termination of a burst of action potentials
How is K,Ca channel (Ca++ activated K+ channel eg IAHP (SK)) altered during repeated AP’s?
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
IAHP can be responsible for ________ (terminate bursts) - generate rhythmic activity in neurons
IAHP 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
What are two hallmark features of I,A?
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)
IA is activated by ________ but to activate one must first remove inactivation by _______ cell
IA is activated by depolarization but to activate one must first remove inactivation by hyperpolarizing cell
IA is blocked by ________ and _________
IA is blocked by 4-aminopyridine (4-AP) and dendrotoxin
How does stimulus intensity affect whether IA can be activated?
With a weak input, membrane repolarization (AHP) is prominent and allows IA to recover from inactivation
With a strong input, IA cannot recover (voltage doesn’t reach sufficiently negative level) so AP’s fire more readily
What controls the activity of inward rectifier channels?
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
Key functions of inward rectifier K+ channels?
- 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 KIR channels allow Ca++ channel activity to maintain a depolarized membrane voltage
