PBL 4 - membrane excitability Flashcards

1
Q

where is K+ most abundant?

A

inside cells (98%) — only 2% in extracellular fluid/blood plasma

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2
Q

what is the normal range of K+?

A

3.5-5mM

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3
Q

what are 2 the terms used to describe when the K+ gradient is disrupted?

A

1) hyperkalemia

2_ hypokalemia

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4
Q

what are some causes of hyperkalemia?

A
  • excessive intake
  • decreased renal removal (renal failure, adrenal disease, medications eg. ACE inhibitors or NSAIDs)
  • tissue damage and release from stores
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5
Q

what are the effects of hyperkalemia?

A
  • impairment of neuromuscular, GI and cardiac systems — can cause fatal cardiac arrhythmias
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6
Q

what awful cardiac arrhythmia can hyperkalemia cause?

A

ventricular fibrillation — abnormal electrical activity causes quivering ventricles — medical emergency as can go into asystole within seconds

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7
Q

what are some causes of hypokalemia?

A

usually excess K+ loss in urine (diuretics, vomiting, diarrhoea, kidney disease)

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8
Q

what are the effects of hypokalemia?

A
  1. cardiac problems — arrhythmias

2. skeletal muscles dysfunction — myalgia, muscle cramps, respiratory depression

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9
Q

what determines cellular excitability?

A

membrane potential of the cell

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10
Q

what is the membrane potential largely determined by?

A

the gradient of K+ across the cell membrane

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11
Q

what does the Nernst equation describe?

A

how the gradient of K+ can affect the membrane potential

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12
Q

what does this ECG show?

A

ventricular fibrillation

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13
Q

what does this ECG show?

A

ventricular tachycardia

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14
Q

what symptoms do people with hypokalemia present with?

A

weakness and fatigue

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15
Q

how do ions such as K+ cross a cell membrane and why?

A

through ion channels as lipid bilayers of the cell membrane have a low permeability to charged ions

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16
Q

what are the 2 types of membrane-spanning proteins?

A

ion channels and ion pumps

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17
Q

what are the key differences between ion channels and ion pumps?

A
  1. ion pumps — use ATP — pump ions across membrane — create ionic gradients
  2. ion channels — don’t use energy — important in setting membrane potential and action potential
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18
Q

label this ion channel

A
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19
Q

what is the purpose of the ion selectivity filter?

A

only lets a certain ion travel through

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20
Q

what is the purpose of m (activation) gates and h (inactivation) gates?

A

allows the ion channel to open at the suitable time — when the m gate opens, ions travel through before the h gate closes

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21
Q

what causes the m gate to open?

A

when an AP comes along in an excitable cell, it depolarises the cell causing the gate to open

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22
Q

what happens at the same time as the ions start to enter the ion channel?

A

h gate starts to close — closure is very slow

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23
Q

when is the ion channel said to be inactive?

A

when the h gate is closed

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24
Q

what is another name for the inactive state of the ion channel?

A

refractory

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25
Q

what needs to happen for the ion channel to open back up again and when does this occur?

A

h gate needs to be open for the channel to be open — happens when the cell goes back to its RESTING MEMBRANE POTENTIAL

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26
Q

describe the basic structure of sodium, calcium and voltage-gated potassium channels

A
  • made up of 4 subunits
  • each subunit has 6 transmembrane domains S1-S6
  • S1-S6 are connected by a series of intra + extra cellular loops
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27
Q

which transmembrane domain in the subunit is the putative voltage sensor (m gate)?

A

S4

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28
Q

what is the link called between S5 and S6 and what is its role?

A

pore-forming loop —forms pore or hole through the membrane = where ions travel

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29
Q

what is the h gate in terms of the subunits in the membrane?

A

the link between the 3rd and 4th subunit = inactivation (h) gate

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30
Q

what is special about S4?

A

positively charged so may acts as voltage sensor (m gate)

31
Q

how do the subunits look when fitted together?

A
32
Q

why do K+ channels have such a diverse function?

A

not covalently linked —> multiple genes and diversity

33
Q

what type of channels are important in setting the membrane potential?

A

inward rectifier K+ channels (Kir)

34
Q

describe the much more simple structure of Kir channels

A
  • 2 transmembrane domains

- pore forming loop

35
Q

what is the role of Kir channels?

A

conduct ions out of the cell — allow K+ to move out — important in setting resting membrane potential

36
Q

what are the 5 phases of cardiac AP?

A
0 - rapid depolarisation 
1 - early repolarisation 
2 - plateau phase 
3 - repolarisation 
4 - resting membrane potential
37
Q

what is the membrane permeable and impermeable to?

A
  • impermeable to large anionic proteins and organic phosphates
  • permeable to potassium (ion channels) — conc grad which K+ moves down (inside to outside)
38
Q

why does K+ get pulled back into the cell after moving out down its conc grad?

A

removing a single K+ from the cell has made the cell slightly -ve compared to outside of the cell (due to -ve anions in cell that can’t move out) — this forms a slight electrical gradient pulling the K+ back into the cell

39
Q

what is the pull of K+ to move into the cell up its conc grad exactly equal to?

A

the pull of K+ to move into the cell up its concentration gradient is exactly balanced to the pull of K+ to move out of the cell down its concentration gradient

40
Q

what is the equilibrium potential? what equation tells us this?

A

= the amount of -ve charge needed inside the cell to exactly balance the conc gradient
- the Nernst equation tells us this

41
Q

what does the number given by the Nernst equation tell you?

A

how much -ve charge you need to balance the conc gradient

42
Q

what is the equilibrium potential number of K+ given by the Nernst equation?

A
  • 86 mV
43
Q

what is the actual eqm potential for K+ and why is it different to the predicted?

A
  • 80mV — permeable to other ion species

because at rest the membranes are permeable to K+ because the inward rectifying K+ channels are open

44
Q

what equation considers other ion species?

A

Goldman-Hodgkin-Katz equation

45
Q

what is a downward deflection and what is an upward deflection?

A
downward = +ve ions going in 
upward = +ve ions going out
46
Q

what does depolarisation mean in terms of potentials?

A

-ve to more +ve potentials

47
Q

what is phase 0?

A

rapid depolarisation

48
Q

explain phase 0

A
  • stopping permeability to K+ — but doesn’t stop at 0mV so something else is happening too
  • large, rapid influx of Na+ into cell
49
Q

what is the rate of depolarisation (phase 0) determined by?

A

the rate at which Na+ enters the cell

50
Q

what needs to happen to allow the rapid influx of Na+ in phase 0?

A

h gates must be open — cell needs to be at its resting MP so all the h gates are open so when the cell becomes excited, all the Na+ channels can respond, allowing the rapid influx of Na+

51
Q

what are most cells in the heart depolarisation by?

A

sodium current

52
Q

when sodium is rushing in in phase 0, what is happening to the K+ channels?

A

they are closing

53
Q

what brings about depolarisation?

A

the rapid influx of Na+ and the closure of K+ channels

54
Q

how does Ito (cardiac transient outward K+ current) influence AP and the difference between epicardial and endocardial AP?

A

a lot of Ito = shortens AP
little Ito = lengthens AP

the endocardial AP is much longer than the epicardial AP due to this difference in the abundance of Ito

55
Q

describe Ito

A

outward current — allowing K+ to move out of cell to cause repolarisation

56
Q

depolarisation vs repolarisation

A
depolarisation = inward movement of +ve ions 
repolarisation = outward movement of +ve ions
57
Q

what is happening in phase 2 (plateau phase)?

A

potassium is going out and calcium channels are opening

58
Q

what causes the plateau?

A

potassium going out and calcium going in is in balance — MP doesn’t change much

59
Q

Ca++ channels vs Na+ channels

A

calcium channels open and close much more slowly than Na+ channels

60
Q

what does phase 2 plateau allow?

A

the ventricles to contract and refractoriness to re-stimulation to allow time for ventricles to refill

61
Q

what type of Ca++ channels are important in this phase 2?

A

L-type — large conductance, slow inactivation and slow reactivation

62
Q

describe phase 3

A

Ca2+ channels close and Ca2+ is transported out of cell. K+ channels open and rapid K+ outflow returns membrane to its resting potential

63
Q

describe the K+ channels in phase 3 repolarisation

A

delayed rectifier K+ channels (mainly Ikr and Iks) — open towards end of AP

  • Ikr opens a little at the start of repolarisation and fully at the end of AP
  • Ikur (ultra-rapid) — in atrial tissue
64
Q

name 3 other repolarising currents

A
  • chloride currents
  • Na+/K+ ATPase 3Na+ out and 2K+ in therefore outward —> RMP
  • Na+/Ca++ exchanger (bidirectional)
65
Q

what would a graph look like showing the effects of hyperkalemia on the AP and excitability?

A
66
Q

why is the RMP more +ve in hyperkalemic patients?

A

loss of K+ gradient —> depolarisation of RMP (more +ve)

67
Q

what is the effect of hyperkalemia on phase 0 and why does this happen?

A

slower rate of rise (Vmax)

  • membrane potential is depolarised
  • not really at RMP< so some of the h gates are still closed — not all the Na+ channels are ready to open — so when excited, they’re not all ready — slow rise
68
Q

what is the effect of a decreased Vmax on conduction in hyperkalemia? effect on ECG?

A
  • slowing of impulse conduction through myocardium

- prolongs P wave, PR interval and QRS complex of the ECG

69
Q

what 2 things is depolarisation due to (phase 0)?

A
  • due to Na+ influx through the rapid opening of voltage-gated Na+ channels
  • due to K+ channels closing
70
Q

what is the plateau due to mainly?

A

Ca++ influx through the more slowly opening voltage-gated Ca++ channels — L-type

71
Q

what is repolarisation due to?

A

closure of voltage-gated Na+ channels and the opening of multiple types of K+ channels (K+ influx)

72
Q

describe Ito, lkr and Iks K+ channels

A
  • Ito : open in phase 1 to allow an outflow of K+ ions
  • Ikr and Iks : delayed rectifier K+ channels. rapid and slow. these open a little in phase 1 and fully in phase 3 to allow an outflow of K+ ions
73
Q

what prevents the early return of the AP voltage to its resting potential?

A
  • immediately after the onset of the AP, the permeability of the cardiac muscle membrane to K+ decreases
  • the decreased K+ permeability greatly decreases the outflow of +ve K+ during the AP plateau (outflow = repolarisation)