Cyclic adenosine monophosphate (cAMP)−protein kinase A (PKA) signaling controls sinoatrial node cell (SANC) function by affecting the degree of coupling between Ca²⁺ and membrane clocks. PKA is known to phosphorylate ionic channels, Ca²⁺ pump and release from the sarcoplasmic reticulum, and enzymes controlling ATP production in the mitochondria. While the PKA cytosolic targets in SANC have been extensively explored, its mitochondrial targets and its ability to maintain SANC energetic balance remain to be elucidated.

To investigate the role of PKA in SANC energetics, we tested three hypotheses: (i) PKA is an important regulator of the ATP supply-to-demand balance, (ii) Ca²⁺ regulation of energetics is important for maintenance of NADH level and (iii) abrupt reduction in ATP demand first reduces the AP firing rate and, after dropping below a certain threshold, leads to a reduction in ATP. To gain mechanistic insights into the ATP supply-to-demand matching regulators, a modified model of mitochondrial energy metabolism was integrated into our coupled-clock model that describes ATP demand.

Experimentally, increased ATP demand was accompanied by maintained ATP and NADH levels. Ca²⁺ regulation of energetics was found by the model to be important in the maintenance of NADH and PKA regulation was found to be important in the maintenance of intracellular ATP and the increase in oxygen consumption. PKA inhibition led to a biphasic reduction in AP firing rate, with the first phase being rapid and ATP-independent, while the second phase was slow and ATP-dependent. Thus, SANC energy balance is maintained by both Ca²⁺ and PKA signaling.

^{环磷酸腺苷 (cAMP)−蛋白激酶 A (PKA) 信号通过影响 Ca 2+}和膜时钟之间的耦合程度来控制窦房结细胞 (SANC) 功能。已知 PKA 可以磷酸化离子通道、Ca ²⁺泵并从肌浆网释放，以及控制线粒体中 ATP 产生的酶。虽然 SANC 中的 PKA 胞质靶标已被广泛探索，但其线粒体靶标及其维持 SANC 能量平衡的能力仍有待阐明。

为了研究 PKA 在 SANC 能量学中的作用，我们测试了三个假设：(i) PKA 是 ATP 供需平衡的重要调节剂，(ii) Ca ²⁺能量学调节对于维持 NADH 水平很重要，并且(iii) ATP 需求的突然减少首先降低 AP 放电率，并且在降至某个阈值以下后，导致 ATP 减少。为了深入了解 ATP 供需匹配调节器，我们将线粒体能量代谢的修改模型集成到描述 ATP 需求的耦合时钟模型中。

实验表明，ATP 需求增加的同时 ATP 和 NADH 水平保持不变。该模型发现Ca ²⁺能量学调节对于维持NADH 很重要，并且发现PKA 调节对于维持细胞内ATP 和增加耗氧量很重要。PKA 抑制导致 AP 放电率双相降低，第一相快速且不依赖于 ATP，而第二相缓慢且依赖于 ATP。^{因此，SANC 能量平衡由 Ca 2+}和 PKA 信号传导维持。