PBL 4 - membrane excitability Flashcards
where is K+ most abundant?
inside cells (98%) — only 2% in extracellular fluid/blood plasma
what is the normal range of K+?
3.5-5mM
what are 2 the terms used to describe when the K+ gradient is disrupted?
1) hyperkalemia
2_ hypokalemia
what are some causes of hyperkalemia?
- excessive intake
- decreased renal removal (renal failure, adrenal disease, medications eg. ACE inhibitors or NSAIDs)
- tissue damage and release from stores
what are the effects of hyperkalemia?
- impairment of neuromuscular, GI and cardiac systems — can cause fatal cardiac arrhythmias
what awful cardiac arrhythmia can hyperkalemia cause?
ventricular fibrillation — abnormal electrical activity causes quivering ventricles — medical emergency as can go into asystole within seconds
what are some causes of hypokalemia?
usually excess K+ loss in urine (diuretics, vomiting, diarrhoea, kidney disease)
what are the effects of hypokalemia?
- cardiac problems — arrhythmias
2. skeletal muscles dysfunction — myalgia, muscle cramps, respiratory depression
what determines cellular excitability?
membrane potential of the cell
what is the membrane potential largely determined by?
the gradient of K+ across the cell membrane
what does the Nernst equation describe?
how the gradient of K+ can affect the membrane potential
what does this ECG show?
ventricular fibrillation
what does this ECG show?
ventricular tachycardia
what symptoms do people with hypokalemia present with?
weakness and fatigue
how do ions such as K+ cross a cell membrane and why?
through ion channels as lipid bilayers of the cell membrane have a low permeability to charged ions
what are the 2 types of membrane-spanning proteins?
ion channels and ion pumps
what are the key differences between ion channels and ion pumps?
- ion pumps — use ATP — pump ions across membrane — create ionic gradients
- ion channels — don’t use energy — important in setting membrane potential and action potential
label this ion channel
what is the purpose of the ion selectivity filter?
only lets a certain ion travel through
what is the purpose of m (activation) gates and h (inactivation) gates?
allows the ion channel to open at the suitable time — when the m gate opens, ions travel through before the h gate closes
what causes the m gate to open?
when an AP comes along in an excitable cell, it depolarises the cell causing the gate to open
what happens at the same time as the ions start to enter the ion channel?
h gate starts to close — closure is very slow
when is the ion channel said to be inactive?
when the h gate is closed
what is another name for the inactive state of the ion channel?
refractory
what needs to happen for the ion channel to open back up again and when does this occur?
h gate needs to be open for the channel to be open — happens when the cell goes back to its RESTING MEMBRANE POTENTIAL
describe the basic structure of sodium, calcium and voltage-gated potassium channels
- 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
which transmembrane domain in the subunit is the putative voltage sensor (m gate)?
S4
what is the link called between S5 and S6 and what is its role?
pore-forming loop —forms pore or hole through the membrane = where ions travel
what is the h gate in terms of the subunits in the membrane?
the link between the 3rd and 4th subunit = inactivation (h) gate
what is special about S4?
positively charged so may acts as voltage sensor (m gate)
how do the subunits look when fitted together?
why do K+ channels have such a diverse function?
not covalently linked —> multiple genes and diversity
what type of channels are important in setting the membrane potential?
inward rectifier K+ channels (Kir)
describe the much more simple structure of Kir channels
- 2 transmembrane domains
- pore forming loop
what is the role of Kir channels?
conduct ions out of the cell — allow K+ to move out — important in setting resting membrane potential
what are the 5 phases of cardiac AP?
0 - rapid depolarisation 1 - early repolarisation 2 - plateau phase 3 - repolarisation 4 - resting membrane potential
what is the membrane permeable and impermeable to?
- impermeable to large anionic proteins and organic phosphates
- permeable to potassium (ion channels) — conc grad which K+ moves down (inside to outside)
why does K+ get pulled back into the cell after moving out down its conc grad?
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
what is the pull of K+ to move into the cell up its conc grad exactly equal to?
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
what is the equilibrium potential? what equation tells us this?
= the amount of -ve charge needed inside the cell to exactly balance the conc gradient
- the Nernst equation tells us this
what does the number given by the Nernst equation tell you?
how much -ve charge you need to balance the conc gradient
what is the equilibrium potential number of K+ given by the Nernst equation?
- 86 mV
what is the actual eqm potential for K+ and why is it different to the predicted?
- 80mV — permeable to other ion species
because at rest the membranes are permeable to K+ because the inward rectifying K+ channels are open
what equation considers other ion species?
Goldman-Hodgkin-Katz equation
what is a downward deflection and what is an upward deflection?
downward = +ve ions going in upward = +ve ions going out
what does depolarisation mean in terms of potentials?
-ve to more +ve potentials
what is phase 0?
rapid depolarisation
explain phase 0
- stopping permeability to K+ — but doesn’t stop at 0mV so something else is happening too
- large, rapid influx of Na+ into cell
what is the rate of depolarisation (phase 0) determined by?
the rate at which Na+ enters the cell
what needs to happen to allow the rapid influx of Na+ in phase 0?
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+
what are most cells in the heart depolarisation by?
sodium current
when sodium is rushing in in phase 0, what is happening to the K+ channels?
they are closing
what brings about depolarisation?
the rapid influx of Na+ and the closure of K+ channels
how does Ito (cardiac transient outward K+ current) influence AP and the difference between epicardial and endocardial AP?
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
describe Ito
outward current — allowing K+ to move out of cell to cause repolarisation
depolarisation vs repolarisation
depolarisation = inward movement of +ve ions repolarisation = outward movement of +ve ions
what is happening in phase 2 (plateau phase)?
potassium is going out and calcium channels are opening
what causes the plateau?
potassium going out and calcium going in is in balance — MP doesn’t change much
Ca++ channels vs Na+ channels
calcium channels open and close much more slowly than Na+ channels
what does phase 2 plateau allow?
the ventricles to contract and refractoriness to re-stimulation to allow time for ventricles to refill
what type of Ca++ channels are important in this phase 2?
L-type — large conductance, slow inactivation and slow reactivation
describe phase 3
Ca2+ channels close and Ca2+ is transported out of cell. K+ channels open and rapid K+ outflow returns membrane to its resting potential
describe the K+ channels in phase 3 repolarisation
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
name 3 other repolarising currents
- chloride currents
- Na+/K+ ATPase 3Na+ out and 2K+ in therefore outward —> RMP
- Na+/Ca++ exchanger (bidirectional)
what would a graph look like showing the effects of hyperkalemia on the AP and excitability?
why is the RMP more +ve in hyperkalemic patients?
loss of K+ gradient —> depolarisation of RMP (more +ve)
what is the effect of hyperkalemia on phase 0 and why does this happen?
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
what is the effect of a decreased Vmax on conduction in hyperkalemia? effect on ECG?
- slowing of impulse conduction through myocardium
- prolongs P wave, PR interval and QRS complex of the ECG
what 2 things is depolarisation due to (phase 0)?
- due to Na+ influx through the rapid opening of voltage-gated Na+ channels
- due to K+ channels closing
what is the plateau due to mainly?
Ca++ influx through the more slowly opening voltage-gated Ca++ channels — L-type
what is repolarisation due to?
closure of voltage-gated Na+ channels and the opening of multiple types of K+ channels (K+ influx)
describe Ito, lkr and Iks K+ channels
- 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
what prevents the early return of the AP voltage to its resting potential?
- 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)
