FIGURE 9.

Numerical simulations showing the short-term (A–C) and long-term (D–F) effects of mitochondrial inhibition on pacemaker activity. The bar above the traces in A–C denotes MCU inhibition. UP depolarizations, which are present before MCU inhibition, are abolished after MCU block (A). This appears to be due to a build-up in C_S2 (B) which prevents the IP₃R from returning to a susceptible state (C). Long-term simulation, after pacemaker activity cessation, shows membrane hyperpolarization (D) caused by a transient increase in C_S1 (E). The increase in C_S1 is due to the emptying of mitochondrial Ca²⁺ stores over time (F). Note that logarithmic values are plotted for the C_S2 (B) and P_IPR (C) traces, and that the y axis on C_S1 trace (E) is truncated at 0.121 μM.