Abstract
The calcium and calmodulin-dependent protein kinase II (CaMKII) is present in sinoatrial node (SAN) pacemaker cells and is required for physiological “fight or flight” SAN beating rate responses. Inhibition of CaMKII in SAN does not affect baseline heart rate, but reduces heart rate increases in response to physiological stress. CaMKII senses intracellular calcium (Ca2+) changes, oxidation status, and hyperglycemia to phosphorylate substrates that regulate Ca2+-sensitive proteins, such as L-type Ca2+ channels, phospholamban, and cardiac ryanodine receptors (RyR2). All of these substrates are involved in the SAN pacemaking mechanism. Excessive CaMKII activity, as occurs under pathological conditions such as heart failure, ischemia, and diabetes, can promote intracellular Ca2+ overload and reactive oxygen species production. Oxidation of CaMKII (ox-CaMKII) locks CaMKII into a constitutively active configuration that contributes to SAN cell apoptosis and fibrosis. This ox-CaMKII-mediated loss of functional SAN cells contributes to SAN dysfunction (SND) and sudden death. Thus, CaMKII has emerged as a central regulator of physiological SAN responses and a key determinant of SND.
Highlights
The sinoatrial node (SAN) is a specialized region of heart tissue present at the junction of the right atrium and superior vena cava that extends along the cristae terminalis, where it initiates each normal heart beat
The other system involves intracellular Ca2+ machinery that is used for excitation–contraction coupling in mechanically purposed myocardium, but that contributes to rhythmic intracellular Ca2+ oscillations in SAN
This study suggested that another calmodulin inhibitor, W-7, with well documented off target actions had direct effects on If that were independent of Ca2+ and calmodulin
Summary
Reviewed by: Zhandi Liao, University of California, Davis, USA Satoshi Matsuoka, University of Fukui, Japan. CaMKII senses intracellular calcium (Ca2+) changes, oxidation status, and hyperglycemia to phosphorylate substrates that regulate Ca2+-sensitive proteins, such as L-type Ca2+ channels, phospholamban, and cardiac ryanodine receptors (RyR2). All of these substrates are involved in the SAN pacemaking mechanism. Oxidation of CaMKII (ox-CaMKII) locks CaMKII into a constitutively active configuration that contributes to SAN cell apoptosis and fibrosis. This ox-CaMKII-mediated loss of functional SAN cells contributes to SAN dysfunction (SND) and sudden death.
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