Cardiac Action Potential - Phases (APD)

Phase 0 - Rapid Depolarization (Upstroke)

• Ion: Na+ (massive inward current)
• Channel/Gene: Na_V1.5 / SCN5A
• The resting membrane potential of working myocytes is approximately -80 to -90 mV. On reaching threshold, Na_V1.5 channels snap from closed -> open, allowing up to 10^7 Na+ ions/sec to enter.
• The maximal upstroke slope (dV/dt_max or V_max) reflects Na+ current magnitude and is the primary determinant of conduction velocity.
• Na+ channels then rapidly inactivate (~1 ms), ending phase 0.
• A small "late Na+ current" (I_NaL) persists into the plateau in some cells, contributing inward depolarizing current.

Phase 1 - Early Rapid Repolarization ("Notch")

• Ion: K+ (outward, repolarizing)
• Channels: Transient outward K+ channels - I_to1 (K_V4.2/4.3, genes KCND2/KCND3, 4-AP-sensitive) and I_to2 (Ca2+-activated, K_Ca2.1/2.2/2.3, genes KCNN1,2,3)
• At the end of phase 0, membrane potential is positive to E_K, so K+ rushes out, producing a brief downward notch.
• The notch is more prominent in epicardium than endocardium, contributing to transmural repolarization gradients.
• Phase 1 sets the voltage level for the subsequent plateau.

Phase 2 - Plateau

• Balance of inward and outward currents - the most distinctive feature of the cardiac AP
• Inward (depolarizing): L-type Ca2+ current (I_CaL, Ca_V1.2, CACNA1C) - the dominant inward current; also T-type Ca2+ (Ca_V3.2, CACNA1H)
• Outward (repolarizing): Delayed rectifier K+ currents - I_Ks (K_V7.1, KCNQ1/KCNE1), I_Kr (K_V11.1, KCNH2/HERG), I_Kur (K_V1.5, KCNA5, mainly atrial)
• The inward Ca2+ entry during phase 2 triggers calcium-induced calcium release (CICR) from the sarcoplasmic reticulum - this is the mechanism of electromechanical coupling and cellular contraction.
• As Ca2+ channels inactivate and K+ currents (especially I_Kr) build up, the balance tips toward repolarization.

Phase 3 - Final Rapid Repolarization

• Ion: K+ (large outward current)
• Channels: Continued I_Kr and I_Ks, plus inward rectifier I_K1 (K_IR2.1, KCNJ2)
• Delayed rectifier K+ currents have fully activated; Ca2+ channels have inactivated - net current becomes strongly outward.
• Membrane potential returns to resting level (~-80 to -90 mV).
• Refractory period: From phase 0 until repolarization to approximately -60 mV in phase 3, the cell cannot be re-excited. This is the effective refractory period (ERP) and is closely tied to APD.

Phase 4 - Resting Membrane Potential / Diastolic Depolarization

• Ion: K+ (I_K1 - inward rectifier, outward at rest, sets resting potential)
• In working myocytes (ventricle, atria, His-Purkinje): stable resting potential of -80 to -90 mV, maintained by I_K1.
• In pacemaker cells (SA node, AV node): there is no stable phase 4 - instead, a slow spontaneous diastolic depolarization driven by I_f (the "funny current," HCN4, HCN4), which brings the cell back up to threshold for the next AP. This is the mechanism of automaticity.

SA/AV Node: "Slow Response" APs

• Resting potential: only -50 to -65 mV (less negative)
• No fast Na+ current (inactivated at this voltage range)
• Phase 0 upstroke is slow, driven by L-type Ca2+ (not Na+)
• Automatic diastolic depolarization in phase 4 via I_f (pacemaker current)
• Much slower conduction velocity compared to His-Purkinje system

Summary Table

• Braunwald's Heart Disease (10th/12th ed.), Chapter 62: "The Cardiac Action Potential" and "Phases of the Cardiac Action Potential"
• Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapter 34: "The Cardiac Action Potential"