Contents

๐Ÿ“’ Mustroph 2014

CaMKII regulation of cardiac K channels1

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INTRODUCTION

https://www.frontiersin.org/files/Articles/78652/fphar-05-00020-r2/image_m/fphar-05-00020-g001.jpg

  • Ca/calmodulin-dependent protein kinase II (CaMKII) has been identified as an important regulator of ion channels and transporters involved in cardiac excitationโ€“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.

https://www.frontiersin.org/files/Articles/78652/fphar-05-00020-r2/image_m/fphar-05-00020-t001.jpg

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)

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  • 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 CaMKIIฮด 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

Reference


  1. Mustroph J, Maier LS, Wagner S. CaMKII regulation of cardiac K channels. Front. Pharmacol. 2014;5:20. doi:10.3389/fphar.2014.00020. PMC3930912↩︎