CaMKII phosphorylation of L type Ca
CaMKII phosphorylation of L-type Ca2+channels alters channel gating by increasing open probability. CaMKII increases the window current of ICa-L, increasing the probability of the channels reopening during phase 2 tgf beta receptor 1 and predisposing to early afterdepolarizations. Recently identified phosphorylation sites of L-type Ca2+ channels include Ser1512 and Ser1570 of the α-subunit CaV1.2 and Thr498 of the accessory β2a-subunit [57,58]. However, the relative relationship between these phosphorylation sites and ICa-L changes remains unclear. Interestingly, a study using rabbit ventricular myocytes overexpressing β2a demonstrated that Thr498 phosphorylation reduced cell survival . The authors suggested that CaMKII phosphorylation of β2a could initiate a pathological cascade of enhanced cellular Ca2+ entry causing excessive SR Ca2+ release, leading to reduced cell survival.
CaMKII action on voltage-gated Na+ channel subunit NaV1.5 has also been implicated as a potent contributor to HF progression. HF is associated with increased intracellular Na+ concentrations ([Na+]i). The rise in [Na+]i increases Ca2+ influx via reverse model NCX during systole and limits Ca2+ efflux via forward NCX during diastole, leading to intracellular Ca2+ overload. Increases in diastolic Ca2+ levels cause abnormal left ventricular relaxation and diastolic dysfunction. The major pathway for increased Na+ influx is through Na+ channels. Although Na+ channels open and close rapidly, a non-inactivated, persistent component of Na+ current (INa-L) is enhanced in HF. In tachypacing-induced HF dogs, the difference in INa-L before and after CaMKII inhibitor KN93 was greater in failing myocytes than in the control . CaMKII associates with and phosphorylates NaV1.5 at the linker between domain I and II [61,62]. A recent study in rat ventricular myocytes reported that an increase in INa-L caused an elevation in the intracellular Ca2+ levels and activation of CaMKII, which, in turn, phosphorylated NaV1.5, further promoting INa-L and subsequent sodium-dependent Ca2+ overload .
Therapeutic consideration From the results of larger-scale clinical trials demonstrating a high frequency of HF and non-sudden cardiac death in patients with shocked VTAs, optimization of HF therapy is strongly recommended [5,7]. Because β-blockers, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and spironolactone reduce cellular Ca2+ load and ROS production, Devonian HF medications are likely to possess CaMKII inhibitory actions. This notion, although not proven, might be supported by some experimental studies. Metoprolol reverses the hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function . The angiotensin-receptor blocker valsartan restores SR function along with attenuation of RyR2 hyperphosphorylation and a decrease in abnormal SR Ca2+-leak . Therapeutic approaches targeting leaky RyR2 and INa-L have recently emerged. RyR2 stabilizers JTV-519 and the more specific analog S107 reduce SR Ca2+ leak by increasing the binding affinity for FKBP12.6 to RyR2 [66,67], whereas dantrolene, a therapeutic agent for malignant hyperthermia, reduces SR Ca2+ leak by correcting domain unzipping . RyR2 stabilization with these agents improves contractile function in dogs with HF . Carvedilol  and INa-L blocker ranolazine (not available in Japan)  have been demonstrated to reduce RyR2 single-channel open probability. Low-dose carvedilol prevents Ca2+ leak via RyR2 stabilization in HF dogs . Inhibition of INa-L with ranolazine exerts beneficial effects on systolic and diastolic HF in experimental models . These agents might also mitigate CaMKII overactivity by improving aberrant Ca2+ homeostasis. In clinical situations where interventions targeting CaMKII are not available, maximization of both conventional and newly developed HF regimes should be underscored for the management of ICD patients at risk.