Caveolin-3 is required for regulation of transient outward potassium current by angiotensin II in mouse atrial myocytes

Angiotensin II (AngII) is a key mediator of the renin-angiotensin system and plays an important role in the regulation of cardiac electrophysiology by affecting various cardiac ion currents, including transient outward potassium current Ito. AngII receptors and molecular components of Ito, Kv4.2 and Kv4.3 channels, have been linked to caveolae structures. However, their functional interaction as well as the importance of such proximity within 50-100nm caveolar nanodomains, remain unknown. To address this, we studied the mechanisms of Ito regulation by AngII in atrial myocytes of wild type (WT) and cardiac-specific caveolin-3 (Cav3) conditional knock-out (Cav3KO) mice. We showed that in WT atrial myocytes, a short-term (2 hours) treatment with AngII (5 µM) significantly reduced Ito density. This effect was prevented (1) by a 30-min pretreatment with a selective antagonist of AngII receptor 1 (Ang1R) losartan (2 µM) or (2) by a selective inhibition of protein kinase C (PKC) by BIM1 (10 µM). The effect of AngII on Ito was completely abolished in Cav3-KO mice, with no change in a baseline Ito current density. In WT atria, Ang1Rs co-localized with Cav3, and the expression of Ang1Rs was significantly decreased in Cav3KO in comparison with WT mice while no change in Kv4.2 and Kv4.3 protein expression was observed. Overall, our findings demonstrate that Cav3 is involved in the regulation of Ang1R expression and is required for modulation of Ito by AngII in mouse atrial myocytes.

Calcineurin Aβ gene knockdown inhibits transient outward potassium current ion channel remodeling in hypertrophic ventricular myocyte

It has been shown that the activation of calcineurin is involved in regulating ion channel remodeling in hypertrophic cardiomyocytes. But the precise role of calcineurin in the regulation of transient outward potassium current (I to), an ion channel associated with fatal arrhythmia, remains controversial. This study aimed to examine the effects of calcineurin Aβ (CnAβ) gene knockdown on I to channel remodeling and action potential duration (APD) in the hypertrophic ventricular myocytes of neonatal rats. Results showed that phenylephrine stimulation caused hypertrophy of ventricular myocytes, upregulation of CnAβ protein expression, downregulation of Kv4.2 mRNA and protein expression, a decrease in I to current density, and prolongation of APD. CnAβ gene knockdown significantly inhibited the effects of phenylephrine stimulation. Our data indicate that CnAβ gene knockdown can inhibit I to channel remodeling and APD prolongation in hypertrophic neonatal rat ventricular myocytes. This finding suggests that calcineurin may be a potential target for the prevention of malignant ventricular arrhythmia in a hypertrophic heart.

The transient outward potassium current plays a key role in spiral wave breakup in ventricular tissue

Spiral wave reentry as a mechanism of lethal ventricular arrhythmias has been widely demonstrated in animal experiments and recordings from human hearts. It has been shown that in structurally normal hearts, spiral waves are unstable, breaking up into multiple wavelets via dynamical instabilities. However, many of the second-generation action potential models give rise only to stable spiral waves, raising issues regarding the underlying mechanisms of spiral wave breakup. In this study, we carried out computer simulations of two-dimensional homogeneous tissues using five ventricular action potential models. We show that the transient outward potassium current (Ito), although it is not required, plays a key role in promoting spiral wave breakup in all five models. As the maximum conductance of Ito increases, it first promotes spiral wave breakup and then stabilizes the spiral waves. In the absence of Ito, speeding up the L-type calcium kinetics can prevent spiral wave breakup, however, with the same speedup kinetics, spiral wave breakup can be promoted by increasing Ito. Increasing Ito promotes single-cell dynamical instabilities, including action potential duration alternans and chaos, and increasing Ito further suppresses these action potential dynamics. These cellular properties agree with the observation that increasing Ito first promotes spiral wave breakup and then stabilizes spiral waves in tissue. Implications of our observations to spiral wave dynamics in the real hearts and action potential model improvements are discussed.

Inhibition of cardiac potassium currents by oxidation-activated protein kinase A contributes to early afterdepolarizations in the heart

Oxidation-activated PKA type I inhibits transient outward potassium current ( Ito) and inward rectifying potassium current ( IK1) and contributes to ROS-induced APD prolongation as well as generation of early afterdepolarizations in murine ventricular cardiomyocytes.

Inhibition of Kv2.1 Potassium Channels by MiDCA1, A Pre-Synaptically Active PLA2-Type Toxin from Micrurus dumerilii carinicauda Coral Snake Venom

MiDCA1, a phospholipase A2 (PLA2) neurotoxin isolated from Micrurus dumerilii carinicauda coral snake venom, inhibited a major component of voltage-activated potassium (Kv) currents (41 ± 3% inhibition with 1 μM toxin) in mouse cultured dorsal root ganglion (DRG) neurons. In addition, the selective Kv2.1 channel blocker guangxitoxin (GxTx-1E) and MiDCA1 competitively inhibited the outward potassium current in DRG neurons. MiDCA1 (1 µM) reversibly inhibited the Kv2.1 current by 55 ± 8.9% in a Xenopus oocyte heterologous system. The toxin showed selectivity for Kv2.1 channels over all the other Kv channels tested in this study. We propose that Kv2.1 channel blockade by MiDCA1 underlies the toxin’s action on acetylcholine release at mammalian neuromuscular junctions.

Early repolarisation syndrome – where do we stand now?

Early repolarization syndrome is associated with high risk of lethal arrhythmias. There is still a huge lack of evidence in the area of arrhythmogenesis, genetics and molecular mechanisms of J wave syndromes. Early repolarization is characterized by so called J waves which are seen in infero-lateral leads (II, III, aVF, V4, V5, V6). The early repolarization is dependent on rapid outward potassium current. One of the latest thesis on ventricular arrhythmias induction are various refraction times of Ito currents in epicardium and endocardium forming electrical current, which induces phase 2 re-entry arrhythmias. The treatment after cardiac arrest survival is implantation of cardioverter-defibrillator. There are few pharmacological methods of repolarization pattern restoration. Reviews of premature ventricular contractions inducing ventricular fibrillation, mainly in Brugada syndrome, ablation have been presented. The main prophylactic issue is to identify the most endangered patients.