Cardiac action potential and excitation-contraction coupling

At a glance

• The ventricular action potential has five phases. Sodium drives the upstroke, a calcium-potassium balance holds the plateau and potassium repolarises.
• Pacemaker cells lack IK1, rest at about -60 mV and depolarise spontaneously through the funny current (If) and calcium currents. Their upstroke is calcium, not sodium.
• Excitation-contraction coupling is calcium-induced calcium release: L-type calcium entry opens RyR2 on the sarcoplasmic reticulum, calcium binds troponin C, and cross-bridges cycle.
• Relaxation needs calcium removal, mostly by SERCA2a (regulated by phospholamban) and the Na/Ca exchanger.
• Paper 1 uses this to explain ECG changes of potassium and calcium disorders, channelopathies, digoxin toxicity and the action of antiarrhythmics.

The ventricular action potential

Phase	Main current	Channel (gene)	Clinical link
4 (rest, -90 mV)	IK1 outward	Kir2.1 (KCNJ2)	Andersen-Tawil syndrome; set by serum K
0 (upstroke)	INa inward	Nav1.5 (SCN5A)	Class I drugs; Brugada (loss); LQT3 (late current gain)
1 (early repolarisation)	Ito outward	Kv4.3	Larger in RV epicardium: the J-point notch, Brugada pattern
2 (plateau)	ICa-L in, IKs and IKr out	Cav1.2; KCNQ1, KCNH2	Calcium entry triggers contraction; isoelectric ST segment
3 (repolarisation)	IKr and IKs outward	hERG (KCNH2), KCNQ1	T wave; QT prolongation by IKr block

During phase 0 to mid-phase 3 the cell is absolutely refractory because sodium channels are inactivated. They recover as the membrane repolarises, giving a relative refractory period late in phase 3. A stimulus on the T wave can land on tissue with uneven recovery and start VF (R-on-T).

Worked example: potassium and the resting potential

The Nernst equation at 37°C: E_K = 61.5 × log10([K]out / [K]in).

• Normal: [K]out 4, [K]in 140 mmol/L. E_K = 61.5 × log10(0.0286) = 61.5 × (-1.54) = -95 mV.
• Hyperkalaemia, [K]out 8 mmol/L: E_K = 61.5 × log10(0.057) = 61.5 × (-1.24) = -76 mV.

A resting potential 19 mV less negative leaves many sodium channels inactivated. The upstroke slows (wide QRS, then sine wave, then asystole or VF). High extracellular K also increases IKr conductance, so repolarisation speeds up and the T wave becomes tall and peaked. IV calcium doesn't change the potassium; the classic explanation is that it raises the threshold potential and restores the gap between rest and threshold. That account rests on old experimental data, and calcium probably restores conduction in other ways too, but it remains the expected exam answer. See hyperkalaemia.

Hypokalaemia does the reverse on repolarisation: lower IKr conductance prolongs phase 3, producing ST depression, flat T waves, U waves and early afterdepolarisations. It also increases digoxin binding to the Na/K ATPase, because potassium competes with digoxin at the same site. Loop and thiazide diuretics cause hypomagnesaemia as well, which worsens both digoxin toxicity and the risk of torsades. IV magnesium (2 g, 8 mmol) is first-line for torsades, even with a normal serum level; see long QT syndrome.

The pacemaker action potential

• Phase 4 rises slowly from about -60 mV. The membrane clock is If (HCN4), opened by hyperpolarisation. The calcium clock is spontaneous SR calcium release driving inward Na/Ca exchanger current. T-type calcium current finishes the ramp.
• Phase 0 is the L-type calcium current, slow, which is why the AV node conducts slowly and decrementally.
• Sympathetic stimulation raises cAMP, which increases If directly and steepens phase 4. Vagal acetylcholine and adenosine open IK,ACh (GIRK channels), hyperpolarise the cell and lower cAMP.

Drug	Target	Effect
Ivabradine	If	Slows sinus rate only; no effect on contractility or AV conduction
Verapamil, diltiazem	L-type calcium (nodal)	Slow sinus rate and AV conduction; negative inotropes
Adenosine	A1 receptor, IK,ACh	Transient AV block; terminates AV node-dependent SVT
Atropine	Muscarinic M2	Speeds sinus rate and AV nodal conduction; no effect below the His

Excitation-contraction coupling

1. The action potential travels down the T-tubules.
2. L-type calcium channels open during phase 2. This small calcium influx opens nearby RyR2 channels: calcium-induced calcium release.
3. Cytosolic calcium rises about tenfold and binds troponin C. Tropomyosin moves off myosin-binding sites on actin and cross-bridges cycle.
4. Relaxation: in humans about 70% of calcium returns to the SR by SERCA2a and about 28% leaves the cell through the Na/Ca exchanger (3 Na in for 1 Ca out). The sarcolemmal calcium pump and mitochondria remove the rest.

Beta-1 stimulation acts through Gs, cAMP and PKA, phosphorylating the L-type channel and RyR2 (more calcium in, more force), phospholamban (faster SERCA uptake, faster relaxation) and troponin I (faster calcium release from troponin).

How drugs and diseases act on the coupling

• Digoxin: Na/K ATPase block raises intracellular sodium, less calcium leaves through the exchanger, and SR calcium load rises. In toxicity, calcium overload causes delayed afterdepolarisations: atrial tachycardia with block, bidirectional VT. Acute overdose causes hyperkalaemia because the pump is blocked in every cell. Correct potassium and magnesium; digoxin Fab is the treatment for life-threatening toxicity (see digoxin poisoning). See also amiodarone, digoxin and adenosine.
• Catecholaminergic polymorphic VT: RyR2 (or calsequestrin) mutations leak SR calcium under adrenergic drive, giving DADs and bidirectional VT on exercise.
• Levosimendan sensitises troponin C to calcium; milrinone blocks PDE3 to raise cAMP; mavacamten inhibits cardiac myosin ATPase in obstructive hypertrophic cardiomyopathy.
• Heart failure downregulates SERCA2a and leaks calcium from RyR2, which slows relaxation, weakens contraction and promotes arrhythmia.

How it's tested

• Explain the ECG sequence of hyperkalaemia, or why calcium gluconate works before the potassium falls.
• Match a channelopathy to its current and trigger: long QT syndrome types 1 to 3, Brugada syndrome (SCN5A loss, unmasked by fever and sodium-channel blockers), CPVT.
• Predict the effect of a drug class on a phase. Vaughan Williams is covered in antiarrhythmic drug classification.
• Explain why hypokalaemia (and hypomagnesaemia from the same diuretic) makes digoxin toxicity more likely, or why a drug that blocks hERG prolongs the QT and why magnesium treats torsades.
• Contrast cardiac and skeletal coupling: the heart stops contracting in calcium-free solution; skeletal muscle doesn't.

Pitfalls

• The SA and AV node upstroke is calcium, so class I sodium-channel blockers have little effect on nodal conduction, and calcium-channel blockers have a large one.
• Hyperkalaemia depolarises the resting membrane but makes the cell less excitable, because inactivated sodium channels can't fire.
• Peaked T waves reflect faster repolarisation from higher IKr conductance, not "more potassium in the cell".
• Phospholamban inhibits SERCA when dephosphorylated; PKA phosphorylation releases the brake.
• Most of the contractile calcium comes from the SR, but without the trigger influx through L-type channels the SR doesn't release.