In cardiomyocytes, Ca2+ entry through voltage-dependent Ca2+ channels (VDCCs) binds to and activates RyR2 channels, resulting in subsequent Ca2+ release from the sarcoplasmic reticulum (SR) and cardiac contraction. Previous research has documented the molecular coupling of small-conductance Ca2+-activated K+ channels (SK channels) to VDCCs in mouse cardiac muscle. Little is known regarding the ...

The cardiac ryanodine receptor (RyR2) is the major calcium (Ca ) release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes. During excitationcontraction, coupling intracellular Ca stored in the SR is released via RyR2 to activate muscle contraction. In the heart, excitation-contraction coupling is activated by Ca influx via the L-type Ca channel that activates RyR2, a process referre...

Ryanodine receptors (RyRs) are channels governing the release of Ca(2+) from the sarcoplasmic or endoplasmic reticulum. They are required for the contraction of both skeletal (RyR1) and cardiac (RyR2) muscles. Mutations in both RyR1 and RyR2 have been associated with severe genetic disorders, but high-resolution data describing the disease variants in detail have been lacking. Here we present t...

Objective: In the present study, we investigate the role of the NH2-terminal region of RyR2 in and the impact of a number of cardiomyopathy-associated RyR2 mutations on the termination of Ca release. Methods and Results: The 35-residue exon-3 region of RyR2 is associated with dilated cardiomyopathy. Single-cell luminal Ca imaging revealed that the deletion of the first 305 NH2-terminal residues...

The multifunctional Ca 2 /calmodulin-dependent protein kinase II (CaMKII ) modulates cardiac muscle function by regulating Ca transport proteins and nuclear signaling molecules. Aberrant activity of CaMKII is implicated in heart disease. In this issue, Yang et al1 report that acute overexpression of constitutively active splice variant CaMKII C phosphorylates the cardiac ryanodine receptor ion ...

Despite the important role of electromechanical alternans in cardiac arrhythmogenesis, its molecular origin is not well understood. The appearance of calcium alternans has often been associated to fluctuations in the sarcoplasmic reticulum (SR) Ca loading. However, cytosolic calcium alternans observed without concurrent oscillations in the SR Ca content suggests an alternative mechanism related...

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2 channels and to what extent...

In this issue of Circulation Research, Cherednichenko et al1 describe an NADH oxidase activity that regulates the ryanodine receptor ion channel (RyR2) in cardiac muscle. Mammalian tissues express three closely related 560-kDa ryanodine receptors (RyRs) encoded by separate genes. RyR1 is the predominant isoform in skeletal muscle, and RyR2 predominates in heart. RyR3 is widely expressed at low ...

175 JGP | Research News The human heart beats more than 2.5 billion times over the course of an average lifetime. The ryanodine receptor type 2 (RyR2) helps regulate these beats, and mutations in this ion channel cause catecholamine-induced polymorphic ventricular tachycardia (CPVT). Uehara et al. describe how one particular disease-causing mutation dramatically affects RyR2 behavior (1). The a...

RATIONALE Flecainide, a class 1c antiarrhythmic, has emerged as an effective therapy in preventing arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) refractory to β-adrenergic receptor blockade. It has been proposed that the clinical efficacy of flecainide in CPVT is because of the combined actions of direct blockade of ryanodine receptors (RyR2) and Na(+...