RyR-NCX-SERCA local cross-talk ensures pacemaker cell function at rest and during the fight-or-flight reflex

Rationale: A recent study published in Circulation Research by Gao et al used sinoatrial node (SAN)-targeted, incomplete Ncx1 knockout in mice to explore the role of the Na+/Ca2+ exchanger (NCX) in cardiac pacemaker. The authors concluded that NCX is required for increasing sinus rates, but not for maintaining resting heart rate. This conclusion was based, in part, on numeric model simulations performed by Gao et al that reproduced their experimental results of unchanged action potentials in the knockout SAN cells. The authors, however, did not simulate the NCX current (INCX), that is, the subject of the study. Objective: We extended numeric examinations to simulate INCX in their incomplete knockout SAN cells that is crucial to interpret the study results. Methods and Results: INCX and Ca2+ dynamics were simulated using different contemporary numeric models of SAN cells. We found that minimum diastolic Ca2+ levels and INCX amplitudes generated by remaining NCX molecules (only 20% of control) remained almost unchanged. Simulations using a new local Ca2+ control model indicate that these powerful compensatory mechanisms involve complex local cross-talk of Ca2+ cycling proteins and NCX. Specifically, lower NCX expression facilitates Ca2+-induced Ca2+ release and larger local Ca2+ releases that stabilize diastolic INCX. Further reduction of NCX expression results in arrhythmia and halt of automaticity. Conclusions: Remaining NCX molecules in the incomplete knockout model likely produce almost the same diastolic INCX as in wild-type cells. INCX contribution is crucially important for both basal automaticity of SAN cells and during the fight-or-flight reflex. (Circ Res. 2013;113:e94-e100.).