Figure 1.

Schematic illustration of pacemaker mechanisms in the sinus node myocyte. Sinus node action potential is preceded by a slow diastolic depolarization (DD) which brings the membrane potential up to the threshold level for excitation. The DD is a result of synergistic interaction between the membrane voltage-clock and the subcellular Ca²⁺-clock. The membrane voltage-clock comprises plasma membrane bound, voltage-dependent ion channels and their corresponding ionic currents. At the beginning of the DD, there is voltage-dependent deactivation of outward K⁺ currents (I_{K, r} and I_{K, s}) and activation of inward currents: hyperpolarization-activated cyclic nucleotide-gated (HCN) or funny current (I_f), T-type Ca²⁺ current (I_{Ca, T}) and L-type Ca²⁺ current (I_{Ca, L}) amongst others. The Ca²⁺-clock contributes to sinus node DD through localized Ca²⁺ release from the sarcoplasmic reticulum via the ryanodine receptor (RYR2). Increased levels of cytosolic Ca²⁺ activates the electrogenic Na⁺–Ca²⁺ exchanger (NCX1) generating an inward current (I_NaCa) that imparts a steep, exponential increase to the late phase of DD. SERCA2 refills the sarcoplasmic reticulum with Ca²⁺ and is hence crucial to sinus node pacemaking.