CaMKII in sinoatrial node physiology and dysfunction

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.

Human sinoatrial node structure: 3D microanatomy of sinoatrial conduction pathways

“…SAN automaticity and conduction depends on the unique heterogeneous distribution of intracellular ion channels, Ca 2+ handling proteins and autonomic receptors within the SAN 10-12 as well as the unique structure of the SAN complex 13 . The specialized microanatomy allows the small SAN to pace the large atria efficiently by maintaining a balanced source-sink relationship 14 .…”

Contribution of small conductance K+ channels to sinoatrial node pacemaker activity: insights from atrial‐specific Na+/Ca2+ exchange knockout mice

“…), ankyrin‐B loss‐of‐function families (Le Scouarnec et al . ), heart failure, ischaemia, diabetes (Wu & Anderson, ) and digitalis intoxication (Gonzalez & Vassalle, ). Classical SAN dysfunction (e.g.…”

Contributions of cardiac “funny” (f) channels and sarcoplasmic reticulum Ca2+in regulating beating rate of mouse and guinea pig sinoatrial node

“…There may also be effects via CaMKII that involve SR‐released Ca 2+ (Wu et al. ). In addition, SR‐dependent effects on L‐type Ca 2+ currents thought to act via AC1 and/or AC8 in atrial myocytes have been recently described (Collins and Terrar ).…”

“…These include voltage-gated Ca 2+ channels, NCX (at least indirectly as a consequence of increased subsarcolemmal Ca 2+ ), phospholamban/SERCA, voltage-gated K channels, and sustained inward current channels (Capel and Terrar 2015b). There may also be effects via CaMKII that involve SR-released Ca 2+ (Wu et al 2014). In addition, SR-dependent effects on L-type Ca 2+ currents thought to act via AC1 and/or AC8 in atrial myocytes have been recently described (Collins and Terrar 2012).…”