Lecture 3: Cardiac Muscle Cell: Electro-Mechanical Coupling
•
•
•
Tiny ionic changes can determine the functional fate of a cell
If one cell goes wrong, the whole heart goes wrong
Comes down to a handful of ions being moved in the wrong direction at the wrong time to the wrong place
Cardiomyocyte Ultrastructure
• The structure of the cardiac muscle cells
• Emphasises that the sarcolemma winds in and out along the surface to create the t-tubule
• The t-tubule is an expansion of the external membrane
• Can conduct the AP into the interior regions
• Close to t-tubule structure inside the surface membrane is the SR where calcium is stored
Ventricular Electrical Activity
• AP from ventricular myocyte
• Big proteins in the membrane have positive and negative charges
• Neighbouring cells or tissues can change the electrical composition
• Some proteins in membranes can change their shape
and create a pore to allow things to enter/exit the cell
• The shape of the pore defines what can come through
• The fast sodium channel opens quickly with a membrane
change
• Opens quickly when it feels a membrane change around
it
• Na+ rushes into the cell
o [Na+]out = 145mM
o [Na+]in = 10mM
• Membrane potential goes up
• L-type Ca2+ channels open to allow calcium in
• Slow channel as it takes long to reorganise itself in the
membrane
• Calcium ions come into the cardiac myocyte
• Potassium channels open and potassium leaves the cell
o [K+]out = 5mM
o [K+]in = 140mM
• Repolarises the cell
Excitation-Contraction Coupling
Ca2+ In
• SR is close to the surface membrane in the t-tubule
• Small space between them – fuzzy space
o Does not exist in skeletal muscle
• A few ions accumulating can create a concentration difference
• Calcium L-type channels open
• Calcium triggers release of calcium from the SR via the RyR
receptor
• Together, the sources of calcium activate the myofilaments
Shifting cell Ca2+
• Transmembrane Ca2+ Gradients
• [Ca2+]out = 2mM – plasma and EC fluid
• [Ca2+]in = 100nM
•
•
•
•
•
•
•
•
•
•
•
•
•
[Ca2+]sr = 1mM
Energetic measures to keep [Ca2+] inside the cell
Stores potential energy to do work to get a quick response to achieve a functional outcome which sometimes is
about nerve conduction, contraction, exocytosis
Keep a big gradient and suddenly the cell does something to collapse gradient – fast response
Cardiac myocyte defends concentration difference against calcium concentration outside the cell and in the SR
Huge regulatory effort
Ionic Transporters
Pumps cost energy, exchangers are energy free
o Pumps use ATP
o Has a chemical reaction to liberate energy to move something somewhere
▪ Requires metabolic energy
o Transporters/exchangers are energy free
o Respond to concentration gradients across a barrier
o Swap one thing for another if the circumstances are right that make it more energetically favourable
for those things to be swapped
Pumps go one way, exchangers reverse
Electrogenic transporters alter membrane potential
o Net shift of charge has potential to change membrane potential
o Depolarise, repolarise, hyperpolarise
Ca2+ concentration differences = potential energy stored for contraction initiation
o Energy is required to create concentration difference
Having a concentration difference in place between compartments provides for signalling potential and work
potential
Building and rebuilding Ca2+ concentration gradients costs energy (directly and indirectly) and electrical
stability
o Every time there is an activation cycle in the cardiac cell, the concentration gradient is broken down
momentarily
o Needs to be built during the diastole phase so that it’s good to go ahead for the next heart beat
o Costs energy
Ca2+ Out
• SR Ca2+ uptake and sarcolemmal pump are direct energy costs
o Ca2+ ATPase costs energy
• Ca2+ by Na+/ Ca2+ exchange seems free but has indirect energy costs
o Electrogenic
o 1 calcium out for 3 sodium in
o Move the membrane potential by +1mV
o Always depolarising and moving the membrane potential
o Effect on membrane potential stability – can bring closer to AP
• Costs resting membrane stability – closer to threshold trigger = risk of arrhythmia
• Ca2+ ATPase on the membrane
o Present in some species and not others
o Not sure of the importance in humans
Ca2+ Cycling – What Goes in Must Come Out
• Ca2+ influx to cytosol for contraction
o 20% via Ca2+ channels from outside
▪ L-type calcium channels
o 80% from SR from inside
• Ca2+ efflux from cytosol for relaxation
o 19% via Na+/Ca2+ exchange
o 1% via sarcolemmal Ca2+ pump
▪ Ca2+ ATPase
o 80% uptake by SR Ca2+ pump SERCA2
• Normal operation: internal Ca2+ cycling = 4 x external Ca2+ cycling
•
•
On a beat to beat basis need to have steady state
Over a long time window, gradual shifts with pathological consequences
EC Coupling Can go Both Ways
• Have senses
• Exchanger on the surface membrane position – forward mode
• Calcium is high the cytosol for a moment
o Calcium normally relatively low
• Circumstances favour the calcium to be shoved out for the sodium
to come in
• Occurs in the activation cycle
• Reverse mode – conditions can be different
• Make it favourable to push sodium out and calcium in
o Eg/ depolarisation of AP
o Beginning of fast upstroke
o Fuzzy space is small – small number of Na+ can drive reverse mode
o Unknown circumstances, Ca2+ can be supplied for contraction by the reverse mode
o More of it out through forward mode to bring relaxation
Restoring Na+ Levels
• Ca2+ entry early in AP
• May be a small amount normally – maybe a bigger amount pathologically
• Ca2+ exit by NCX dominant
• Both together generate a sodium load
• Problem – how do you get rid of sodium?
• Removed by Na+/K+ ATPase
o On surface membrane and t-tubule structure
• Uses energy
• Sodium is low in the cell due to the work of the pump
• 3Na+ out for 2K+
• Energy involvement and electrogenic consequence
• Getting rid of an extra positive
• The membrane potential will be brought down closer to -90mV
• Transporter is important – housekeeping pump
• Without the pump, the cell would not work at all
Metabolic Acid Production
• The heart muscle cells job is to do contraction, do work, break down ATP, make cross bridges move, other
metabolic process
• Makes acid
• What to do with all that acid produced by metabolic action/contraction?
• Acid ends up as protons
• Cell has to remove acid produced by contraction and action
o Lipolysis and glycolysis makes protons
• Need to keep electrical gradient and proton build up in order
•  Na+/H+ exchanger