Cellular and molecular events Flashcards
Describe how the resting membrane potential is set up
At rest, the membrane of cardiac myocytes are selectively permeable to K+ (open K+ channels)
K+ ions will diffuse down their chemical diffusion gradient (leak) , out of the cell until the chemical gradient is at equilibrium with the electrical gradient.
At this membrane potential, there is no net movement of ions (electrochemical gradient is zero), but there will be a negative membrane potential left inside the cell
The negative membrane potential begins to oppose the further movement of K+ ions outward
This negative membrane potential arises because:
Anions cannot follow, so are left inside the cell
Cell interior becomes negatively charged
What ultimately sets up resting membrane potential?
The permeability of cardiac myocytes to K+ ions at rest
Cardiac myocytes permeable at rest
What role does the sodium potassium ATPase have in cardiac RMP?
- Sets up a gradient of ions across the membrane so the concentration of Na+ is lower inside the c ell compared to out side
- And the concentration of K+ is higher inside the cell, compared to outside.
- You have a concentration gradient for potassium ions
- Because at rest, the membrane of. cardiac myocytes is permeable to potassium ions…
- K+ is high in cell so moves out of cell
- Makes inside negative relative to outside… (insert RMP membrane generation explain action here)
Equilibrium potential for K+
The membrane potential at which electrical and chemical gradients balance (so the electrochemical gradient is zero) and there is no net movement of ions across the membrane.
Why is resting membrane potential not Ek?
Because at rest, there is a very small permeability to other ions, not just potassium ions
BUT K+ is main determinant of RMP
Ek vs RMP of ventricular cardiac myocytes
Ek = -95mV RMP = -80 to -90mV
Special features cardiac myocytes
- They are electrically active, meaning they fire action potentials
- They are electrically coupled to each other (due to gap-junctions, electrical activity (or depolarisation) is able to spread from one cardiac myocyte to a neighbouring cardiac myocyte and they spread throughout the heart as a whole)
(so if you get depolarisation in one part of the heart, it will spread throughout the heart because all the myocytes are electrically coupled to each other)
Electrically coupled to allow syncronized contraction
What triggers action potential?
Depolarisation
What do action potentials trigger? Why is this needed?
- Increase in concentration of Ca2+ in cytoplasm of the cell
- An increase in this calcium is needed to allow actin and myosin interaction
- That interaction/sliding of actin and myosin filaments generates the tension/contraction, that allows the heart to pump blood
Whys is Ca2+ required?
What does it bind to?
Allows actin and myosin interaction (binds to Troponin C)
How long are action potentials in the axons, skeletal muscles, Sino-atrial node and cardiac ventricle? Draw the intracellular recording of action potentials for each one
SA node and Cardiac ventricle have much longer durations of action potentials than axons/skeletal muscle
(the heart has longer durations of action potentials)
100ms vs 0.5ms
Describe the Ventricular cardiac action potential (for my understanding in detail)
Background: Ek is quite negative (around -95mV) and so is the RMP (around -80 to -90mv)
The RMP is due to background K+ channels open at rest
Cardiac myocytes are electrically coupled, so if you get depolarisation spreading from neighbouring myocyte to ventricular myocyte, you get a very rapid depolarisation and then opening of Voltage gated sodium channels
Voltage gated sodium channels open with depolarisation, causing upstroke
The sodium equilibrium potential is very positive
So when the Voltage gated sodium channels open, it drives the membrane potential towards the sodium equilibrium potential
it doesn’t get to Ena because you get an inactivation of sodium channels and an opening of some potassium channels
The potassium ions start to move out of the cell, as the k+ ion channels are open and you get get a slight repolarisation
Then you get a long plateau, due to opening of voltage gated calcium channels and some k+ channels also open (calcium channels open more slowly) .
Due to this opening, you get an influx of calcium into the cells/myocytes and a tiny bit of potassium out. The calcium is not driving the cell that positive because its balanced with the potassium
Calcium channels inactivate and voltage gated potassium channels open
This drives the membrane potential back down towards the potassium equilibrium potential
Draw and describe the changes in membrane potential and ionic currents in the ventricular cardiac action potential
- Spread of depolarisation from neighbouring cells to cardiac myocytes in ventricle to threshold-led potential
- VGSC (voltage-gated Na+ channels) open allowing influx of Na+ causing rapid depolarisation
- Transient K+ efflux once AP is generated causing slight repolarisation
- VGCC (voltage-gated Ca2+ channels) open causing influx of Ca2+ which slows down repolarisation (as Ca2+ influx negates the K+ efflux)
- VGCC inactivate and more voltage-gated K+ channels (VGKCs) open causing rapid repolarisation, returning to the RMP
Draw and describe the PHASES of the ventricular cardiac action potentia
ps. phase 1 is the initial transient repolarisation
What causes depolarisation?
Opening of V gated Na+ channels
What causes slight dip in membrane potetial? (initla repolarisation)
Transient outflow of K+
What sustains plateau phase?
Open V gated Ca2+ channels
some K+ channels are open
What causes repolarisation?
Ca2+ channels inactivate
V gated K+ channels open - K+ moves out
3 phases of Ventricular action potential
0 = Na+ influx
1 = initial transient repolarisation
2 = Ca2+ influx (K+ efflux)
3 = K+ efflux
SA node action potential difference
No stable Resting membrane potential
Slow depolarisation after each cycle
Na+ doesn’t cause fast depolarisation - Ca2+ does
3 phases of SA node action potential
Pacemaker potential (If - funny current) from influx of Na+ (slow depolarisation) Opening of V gated Ca2+ channels (fast depolarisation) Opening of V gated K+ channels (repolarisation)
Pacemaker potential job
Initial slope to threshold - funny current (If)
Activated at negative membrane potentials (lower than -50mV) - more negative more activation
How does SA node achieve transient inflow of Na+?
HCN channels
Hyperpolarisation-activated Cyclic Nucleotide-gated channels
allow influx of Na+
Types of Ca2+ channels SA node
L-type and Transient (T ) type
How is upstroke achieved SA node?
Opening of V gated Ca2+ channels
How is down stroke (repolarisation) achieved in SA node?
Opening V gated K+ channels (leaves)
Innervation SA node
No innervation needed
Natural automaticity
Membrane potential SA node
UNSTABLE (pacemaker potential, funny current)
Action potentials through heart speed
SA node = fastest
Action potential journey
SA node Across atria AV node Bundle of His Purkinje fibres Ventricle contraction
Pacemaker of heart?
SA node
sets rhythm
AP’s through heart
SA node and AV node - fast
Atrial muscle, ventricular muscle and purkinje fibres - slower
What is responsible for contraction?
Spread of action potential
Problems with action potential firing
too slow - bradycardia
fail - asystole
too quickly - tachycardia
random - fibrillation
Hyperkalaemia
High plasma conc (>5.5mmol/L)
Hypokalaemia
Low plasma conc (<3.5mmol/L)
why are cardiac myocytes sensitive to change in K+?
k+ permeability dominates membrane potential
Hyperkalaemia effects
Ek = less negative
Membrane potential depolarises
Inactivates some of Na+ channels
Slows upstroke
Risks hyperkalaemia
Heart stops - asystole
Initial increase in excitability (depolarised)
Extent hyperkalaemia
Mild: 5.5 - 5.9 mmol/L
Moderate: 6.0 - 6.4 mmol/L
Severe: > 6.5mmol/L
Treatment hyperkalaemia
Calcium gluconate
Insulin and glucose
(causes cells to uptake K+)
**Heart needs to be pumping
Effects of hypokalaemia
Lengthens action potential
Delays repolarisation
Problems hypokalaemia
Longer action potentials can cause Early After Depolarisation (EAD’s)
Oscillations in membrane potential
Ventricular fibrillation
(remember shaking in hypothermia like osscilations)
Excitation contraction coupling initial step
Depolarisation opens L type Ca2+ channels in T tubules
What does Ca2+ entering cytosol cause in cardiac cells?
Opens Calcium induced calcium release (CICR) channels in SR
What happens after CICR channels open?
Ca2+ binds to troponin C
Conformational change shifts tropomyosin
Binding site revealed on actin = myosin can bind
How do cardiac myocytes relax?
Ca2+ pumped into SR (via SERCA)
Some exits via membrane (Ca2+ATPase, Na+Ca2+ exchanger)
How is tone of blood vessels controlled?
Contraction and relaxation of vascular smooth muscle cells
tunica media, arteries arterioles and veins
Excitation contraction coupling smooth muscle cells initial stimulation
Noradrenaline activates a1 receptors
or depolarisation opening V gated Ca2+ channels
What does a1 receptor do?
Activates Gaq to produce second messanger IP3
What does IP3 do?
Binds to receptors on sarcoplasmic reticulum
Initiates release of Ca2+
What does Ca2+ once released from cell? (smooth muscle)
Binds to calmodulin
what does calmodulin do?
Activates Myosin light chain kinase (MLCK)
What does MLCK do?
Phosphorylates myosin light chain = allows interaction with actin
How does contraction stop in smooth muscle?
Myosin light chain phosphatase dephosphorylates the myosin light chain
PKA phosphorylates myosin light chain kinase = inactive
How is contraction inhibited? (smooth muscle cell)
PKA (protein kinase A) phosphorylates MLCK and inhibits it
Cardiac muscle vs smooth muscle excitation and contraction
Cardiac:
Action potential allow Ca2+ entry
More Ca2+ then comes from SR
Ca2+ binds to TROPONIN C
Smooth muslce:
Depolarisation/activation of a-adrenoreceptors
Increased intracellular Ca2+
Ca2+ binds to Calmodulin
Activates MLCK - phosphorylates myosin light chain
