📒 Mustroph 2014
CaMKII regulation of cardiac K channels1
- Ca/calmodulin-dependent protein kinase II (CaMKII) has been identified as an important regulator of ion channels and transporters involved in cardiac excitation–contraction coupling under physiological but also pathophysiological conditions
K CHANNELS ARE IMPORTANT REGULATORS OF CARDIAC EXCITABILITY
- Na current : upstroke (phase 0)
- Ito activation results in an early repolarization (notch, phase 1)
- ICa stabilizes the membrane potential during the plateau phase (phase 2). NCX is active.
- delayed rectifying K channels (IKr, IKs, and IKur): Repolarization (phase 3)
- resting membrane potential (phase 4) is stabilized by IK1 and NKA, NCX
- In pacemaker cells, the absence of a stabilizing IK1 is responsible for a more positive resting membrane potential. non-specific cation current If (channel protein HCN) can thus generate diastolic depolarization leading to the generation of APs.
- Reduced function of Kv7.1 and hERG are the hallmark of congential long QT syndrome 1 and 2, respectively . increased triggered activity due to early afterdepolarizations (EADs). ncreased triggered activity is an important consequence of prolonged repolarization.
- Mutation of ATP-sensitive K channel => prominent J wave on the ECG
- Differential K channel expression across the ventricular wall is the basis for transmural dispersion of repolarization (TDR) => positive T wave. Smaler Ito in endocardial cells => longer AP, higher plateau
- If 100% Ito expression was used ( = epicardial myocytes), CaMKII overexpression resulted in a shortening of the AP duration mainly due to a CaMKII-dependent enhancement of Ito. With 10% Ito expression ( = endocardial myocytes), however, AP duration increased because CaMKII-enhanced late INa and L-type Ca current outweighed the effect on the smaller Ito.
CaMKII AND HF
- In human HF, expression and activity of CaMKII is increased.
- (Rats) increased AP duration, disturbed Ca handling, and are prone to ventricular arrhythmias
TRANSIENT OUTWARD K CURRENT (Ito, both fast)
- With 2 time constants (45.6ms and 453.1ms). They are functionally and structurally independent ion currents.
- Reduced Ito density is known to contribute to AP prolongation and prolonged QT intervals
- overexpression of CaMKIIδ in rabbit myocytes increases Ito
- recovery from inactivation of Ito,fast and Ito,slow was enhanced by CaMKII overexpression
- CaMKII-dependent enhancement of Ito may also be important for reactive oxygen-species (ROS) induced arrhythmogenesis.
- Kv4.3 (ion channel of Ito) may function as a reservoir for inactive CaMKII-units and exert an influence on CaMKII activation levels
- Kv4.3 is downregulated in HF while CaMKII is upregulated
INWARDLY RECTIFYING CURRENT (IK1)
- Kir2.1 (KCNJ2), Kir2.2 (KCNJ12), Kir2.3 (KCNJ4), and Kir2.4 (KCNJ14)
- important stabilizers of the resting membrane potential
- Inhibited or activated by calcium (species-dependent): direct ? via CaMKII? via PKC?
- CaMKII-dependent activation of IK1 also comes from rabbit ventricular myocytes.
- Both anti-arrhythmic and pro-arrhythmic
- (Dog) reduced IK1 has been shown to increase the propensity for sudden cardiac death and ventricular tachycardia
- (Rat) wild-type Kir2.1 overexpressing mice that have an increased propensity for ventricular arrhythmias
DELAYED RECTIFYING K CHANNELS (IKr, IKs, IKur)
- Kv1.5 (KCNA5), hERG (KCNH2), and Kv7.1(KCNQ1) => IKur (ultra rapid), IKr (rapid), and IKs (slow), respectively
- IKur is only present in atrial myocardium. CaMKII increases IKur => pro-AF
ATP-SENSITIVE POTASSIUM CURRENT KATP
- Kir6.1 (KCNJ8) and Kir6.2 (KCNJ11)
- ischemic preconditioning
- Inhibited by active CAMKII
- The significance of KATP in HF and arrhythmogenesis is still largely unknown