RYR2 and Arrhythmia: Additionally, CaMKII (Ca2+/calmodulin kinase II), the key mediator of many of the second messenger effects of Ca2+, and RyR2 (ryanodine receptors), which mediates the release of Ca2+ from the cardiac muscle SR into the cytoplasm and, therefore, plays a crucial role in triggering cardiac muscle contraction, are involved in diabetic impaired Ca2+ handling, cardiac arrhythmias and apoptosis [70].