Voltage gated K+

Question 1

List some subtypes of potassium channels.

Answer 1

Characterised by conductance:

1) Large conductance K+ channels - also known as BK, KCa or Maxi-K channels
2) Intermediate (IK) conductance channels
3) Small (SK) conductance channels;

In neurons, SK channels are responsible for the more persistent SLOW afterhyperpolarisation (AHP) observed after action potential discharges; takes a long time for K+to leave the cell.

Question 2

What are the structural features of maxi K channels

Answer 2

Voltage and ligand gated channel

It has a Long COOH terminus ‘tail’ region important for ligand function; hydrophobic segments and linker region between S8/9 are characteristic of the tail.

RCK domain involved in binding Ca2+ which causes opening.

S4 acts as voltage sensor

The S0 (N-terminal) domain is required for b subunit modulation)

Accessory b subunits (b1 - b4) interact with Maxi-K alpha subunit by changing the sensitivity to Ca2+ and voltage, activation kinetics and pharmacology.

The alpha subunit sequence contains phosphorylation sites and additions of SPLICE insertions adds more sites

Therefore, kinases and phosphatases (PKA, PKC & PKG) can regulate his channel

Question 3

How does calcium channels influence gating?

Answer 3

INCREASE CALCIUM, INCREASE OPENING FORCE, K+ efflux.

Question 4

What is maxi-K

Answer 4

Maxi-K channels are expressed everywhere(except heart) and are VOLTAGE DEPENDENT (V is not fixed) and therefore Ca+ DEPENDANT

As the Ca2+ concentration
in the cell increases the
channel requires less
electrical energy to open

in neurons they help SHAPE AP and regulate TRANSMITTER release.

in smooth muscle they help regulate CONTRACTILE activity and tone.

Question 5

What is TREK1?

Answer 5

A K2p family channel that has P loop and only needs TWO subunits TO MAKE A PORE.

WHEN CELL IS AT REST, THEY ARE OPEN

Question 6

How are complex shapes and firing patterns of the A.P made IN NEURONES?

Answer 6

1) Voltage-gated Ca2+ channels allows Ca to enter giving a ‘BURST’ in MP
2) High [Ca] inside activates Ca2+-activated K+ channels
3) [Ca] inside decreases, K channel closes, neurone depolarises
4) another spike as calcium channels open again.

Question 7

How many genes code for these channels?

Answer 7

70 genes. They are the most diverse channel as different subunits arrange in different ways.

6 segments; one pore
2 segments one pore
4segments 2 pore (TREK)

Question 8

What are the key functions relating to the channel

Answer 8

1) Control of cell volume
2) Control of membrane potential and cell excitability
3) Secretion of salts, hormones and neurotransmitters

Question 9

Give some examples of regulating factors.

Answer 9

1) Numerous hormones & transmitters
2) Voltage across membrane
3) Concentration of Ca2+/ ATP in cytoplasm
4) Kinases and phosphatases
5) G-proteins

Question 10

Describe 6 segment channels (S1-6)

Answer 10

There is a VOLTAGE SENSOR in the fourth segment (change SHAPE) and a P region/ loop with certain residues (G) that determine pore SELECTIVITY.

It is the equivalent of a single Na+ domain

Example: hERG channel

Question 11

What are two types of voltage-activated K+ channels distinguished.

Answer 11

1) Inactivating (‘A’) type (displays RAPID inactivaion after opening determined by residues 6-46)

2) Non-inactivating
(delayed rectifier)

Question 12

Describe how inactivation is caused

Answer 12

First 20 aa form a CHARGED/HYDROPHOBIC domain (a ball) and the next 50 residues act as a chain; this is refered to as blocking particle inactivation or N-TYPE INACTIVATION given where is takes place.

The aa of the ball are recepted by the P loop (between S4-5)

the speed of inactivation varies; alpha sununit is slower than b1

Question 13

In what ways can maxi-K be made diverse?

Answer 13

A single gene (Slo) encodes Maxi-K a subunit but due to multiple alternative splice exons in gene there can be diversity.

Question 14

What part of MaxiK determines the sensitivity of calcium?

Answer 14

he alpha subunit TAIL, in particular, the NEGATIVE aa between S9/10 known as the CALCIUM BOWL.

Bowl and RCK interact

Increased Ca+ increases opening force. Voltage sensor will add to force

Question 15

What role does Maxi-K have in cells?

Answer 15

It acts as a negative feedback system

needed for timing bursts of action potentials ie, the refractory period and Afterhyperpolarisation

opened in response to vasoconstriction; closed to relax smooth muscle.

counteracts Hypertention (increases BP)

tunes ear hair frequency that the cell responds to

Question 16

How does Maxi-K channels relax Vascular smooth muscle?

Answer 16

1) Ca+ released
2) [Ca]i increases causing depolarisaion and contraction
3) BK channels activated; K out
4) membrane HYPERPOLARISES
5) calcium channel closes
6) relaxation

Question 17

How do Maxi K channels decrease neuronal excitability?

Answer 17

1) AP into terminal
2) Ca entry through Ca channels opens K+ channel
3) release of neurotransmitter is limited

Blockinng K channel enhances transmitter release

Question 18

Describe the 2 domain Kir family.

Answer 18

Inward rectifiers as they direct K flow inwards more than outwards

Question 19

Describe the 4 domain K2p family (TREK)

Answer 19

weak inward rectifiers and MOST ABUNDANT

Question 20

What factors increase and decrease channel opening of TREK1?

Answer 20

Increasing by many actors (polymodal) internal pH reduction; heating; intracellular lipids; fatty acids; volatile and gas anaesthetics

Decreasing by phosphorylation using PKA.

Question 21

When TREK1 is absent, what was discovered about its functions?

Answer 21

cellular mechanisms of general anaesthesia

needed for neuroprotection (ischemia and epilepsy) from polyunsaturated fatty acids

needed to regulate sensitivity to painful heat and mechanical stimulation.

mood regulation as the KO mice were anti-depressant state.

Question 22

Describe the functions of a ATP-sensitive channel

Answer 22

Channels activity is inhibited by ATP.

1) STRESS SENSING (muscle, neurone)
2) GLUCOSE SENSING (b cells)

Question 23

What are the functions of ATP-sensitive channel?

Answer 23

Channels closed at rest
OPEN IN METABOLIC STRESS (hypoxia)

When it opens, it causes hyperpolarisation and allows cell to recover.

In glucose cells:

1) Contributes to cell resting potential (partially open)
2) closes when glucose concentration is high (and lots of atp made)
3) cell depolarises
4) calcium helps release vesicles of INSULINcausing INSULIN SECRETION in pancreas b cells.

Question 24

Give an example of a drug that inhibits ATP-sensitive channel?

Answer 24

sulphonylureas are used to treat TYPE 2 DIABETES; forces channel closed.

Question 25

What drugs are associated with ATP-sensitive channel?

Answer 25

1) Acivators = Potassium channel openers (KCOs) for example Diazoxide

These can help relax muscles and act as cardioprotective and neuroprotective (as decreases transmitters release)

Question 26

List diseases of K channel caused by mutations

Answer 26

1) Cardiac: Long-QT syndrome
2) Neuronal: Epilepsy
3) Neurodegeneration
4) Metabolic: HI: hyperinsulinemia
5) Diabetes (Type 2

Question 27

How are complex shapes and firing patterns of the A.P made IN CARDIAC

Answer 27

1) resting membrane potential
2) rapid depolarization due to Na entry
3) Na inactivated, so K efflux
4) inward Ca movement also causes K efflux
5) Ca channels close, K channels still open while cell antipolarises