Fig. 3.
Computer simulations of experimental traces using a model that generates LCS (29). Panels are ordered to indicate the flow of causation. (Ai) Increased LCS frequency is in phase with inward INCX and dVm/dt, which precedes Vm and ICa forming an oscillatory feedback pathway as shown by the arrows. (Aii) When Ca2+ load is reduced, Vm oscillates because ICa (and possibly INa) supply the inward current to increase dVm/dt and cause the EAD, as shown. In this case, LCS (and Ca2+) are the consequence of the reactivation of ICa. Note that in this simulation, INCX bears no obvious relation to dVm/dt (unlike the results shown in Ai). Cross-talk between the oscillators shown in Ai and Aii can occur because they contain common mechanisms. (B) Cross-correlograms between Vm and both ICa and INCX from the data shown in part A. The negative peaks in the cross-correlogram (black arrows) reveal both the strength of association (amplitude) and temporal relationship (offset from Vm) between Vm and ICa or INCX (see SI Appendix). (Bi) When Ca2+ load was high, inward INCX preceded Vm oscillations and was more strongly correlated with Vm than ICa. (Bii) Under reduced Ca2+ load, INCX lags behind Vm oscillations. ICa reactivation preceded Vm and so has the required temporal relationship to explain EAD initiation, although some inward INCX may still contribute (13).