Fig. 8.

Pacemaker model of human embryonic cardiomyocytes. During the early phase of DD, there is enough [Ca²⁺]_i to activate IK_Ca, which contributes to the MDP driving force and concurrently activates I_f. The I_f and/or the NCX currents triggered by the cyclical Ca²⁺ release from SR depolarize the membrane to activate L-type Ca²⁺ channels (I_Ca,L) and cause AP cycling. The progressive decrease in [Ca²⁺]_i from early to late DD operated by the NCX-induced Ca²⁺ outflow will gradually reduce IK_Ca and allow inward currents to take over and reach the next AP threshold. Thus, IK_Ca finely balances inward currents of the “voltage” and Ca²⁺ clocks and thereby has a crucial role in shaping the DD and the pacemaker activity.