Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease occurring in patients with a structurally normal heart: the disease is characterized by life threatening arrhythmias elicited by stress and emotion. In 2001 the ryanodine receptor was identified as the gene that is linked to CPVT; shortly after, cardiac calsequestrin was implicated in the recessive form of the same disease. It became clear that abnormalities in intracellular Ca2+ regulation could profoundly disrupt the electrophysiological properties of the heart. In this article we will discuss the molecular basis of the disease and the pathophysiological mechanisms that are impacting clinical diagnosis and management of affected individuals. As of today, the interaction between basic scientists and clinicians to understand CPVT and identify new therapeutic strategies is one of the most compelling examples of the importance of translational research in cardiology.
Abstract-Mutations in the human cardiac Ca 2ϩ release channel (ryanodine receptor, RyR2) gene have recently been shown to cause effort-induced ventricular arrhythmias. However, the consequences of these disease-causing mutations in RyR2 channel function are unknown. In the present study, we characterized the properties of mutation R4496C of mouse RyR2, which is equivalent to a disease-causing human RyR2 mutation R4497C, by heterologous expression of the mutant in HEK293 cells. [ 3 H]ryanodine binding studies revealed that the R4496C mutation resulted in an increase in RyR2 channel activity in particular at low Ca 2ϩ concentrations. This increased basal channel activity remained sensitive to modulation by caffeine, ATP, Mg 2ϩ , and ruthenium red. In addition, the R4496C mutation enhanced the sensitivity of RyR2 to activation by Ca 2ϩ and by caffeine. Single-channel analysis showed that single R4496C mutant channels exhibited considerable channel openings at low Ca 2ϩ concentrations. HEK293 cells transfected with mutant R4496C displayed spontaneous Ca 2ϩ oscillations more frequently than cells transfected with wild-type RyR2. Substitution of a negatively charged glutamate for the positively charged R4496 (R4496E) further enhanced the basal channel activity, whereas replacement of R4496 by a positively charged lysine (R4496K) had no significant effect on the basal activity. These observations indicate that the charge and polarity at residue 4496 plays an essential role in RyR2 channel gating. Enhanced basal activity of RyR2 may underlie an arrhythmogenic mechanism for effort-induced ventricular tachycardia.
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