Pacemaking in cardiac tissue. From IK2 to a coupled-clock system

Initially, diastolic depolarization in Purkinje fibers was explained by deactivation of gK2 in the presence of inward current. Weakness of the hypothesis was a too negative reversal potential, sensitivity to external Na⁺ ions, existence of K⁺ depletion, and fake current during hyperpolarizing clamps. The development of a sinus node preparation of almost microscopic dimensions allowing uniform voltage clamps created new possibilities. Three different groups discovered in this improved node preparation an hyperpolarization induced time-dependent inward current, with a reversal potential positive to the resting potential, carried by a mixture of Na⁺ and K⁺ ions. A new current, If, or funny current was born. It is not the only pacemaker current. The following sequence of currents (membrane clock) has been proposed: diastole starts as a consequence of IK deactivation and If activation; followed by activation of the T-type Ca²⁺ current, Ca²⁺ -induced Ca²⁺ release from the SR, and activation of sodium-calcium exchange current with further depolarization of the membrane till threshold of the L-type Ca²⁺ current is reached. The release of Ca²⁺ can also occur spontaneously independently from a T-type Ca²⁺ current. The system acts then as a primary intracellular clock. The review is completed by description of an evolution in the direction of biological pacing using induced pluripotent stem cells or transcription factors. See also: https://doi.org/10.14814/phy2.13860 & https://doi.org/10.14814/phy2.13861.