Cardiac and skeletal muscle disorders caused by mutations in the intracellular Ca2+ release channels

Abstract

Here we review the current knowledge about the mutations of the gene encoding the cardiac ryanodine receptor (RyR2) that cause cardiac arrhythmias. Similarities between the mutations identified in the RyR2 gene and those found in the gene RyR1 that cause malignant hyperthermia and central core disease are discussed. In vitro functional characterization of RyR1 and RyR2 mutants is reviewed, with a focus on the contribution that in vitro expression studies have made to our understanding of related human diseases.

Figure 1

Schematic showing the predicted structure of the cardiac ryanodine receptor, RyR2, including the sites of interaction with ancillary proteins and the phosphorylation sites. Calsequestrin, junctin, and triadin, proteins interacting with ryanodine receptor in the SR, are also depicted. PP, protein phosphatase; P, phosphorylation sites; CaM, calmodulin; CaMKII, calmodulin-dependent protein kinase II. Adapted with permission from the Journal of Molecular and Cellular Cardiology (13).

Figure 2

Exercise stress test in a patient with polymorphic VT and RyR2 mutation. Ventricular arrhythmias are observed with a progressive worsening during exercise. Typical bidirectional VT develops after 3 minutes of exercise with a sinus heart rate of approximately 120 bpm. Arrhythmias rapidly recede during recovery.

Figure 3

Bar graph showing the similar clustering of mutations in RyR1 (including both MH and CCD phenotypes) and RyR2 (both CPVT and ARVD2).

Figure 4

Representation of a cardiac action potential, showing DADs. DAD amplitude increases and DAD coupling interval decreases upon cycle length (CL) reduction. With further increase in frequency of stimulation, an automatic beat is generated from the DAD.

Figure 5

Bidirectional VT and ventricular fibrillation in CPVT. (A) ECG recording of bidirectional VT degenerating into ventricular fibrillation in a CPVT patient. (B) ECG recording of a bidirectional VT degenerating into ventricular fibrillation in a RyR2⁺/RyRR4496C mouse.