In the RyR2R4496C mouse model of CPVT, β-adrenergic stimulation induces ca waves by increasing SR Ca content and not by decreasing the threshold for Ca Waves

Takeshi Kashimura, Sarah J. Briston, Andrew W. Trafford, Carlo Napolitano, Silvia G. Priori, David A. Eisner, Luigi A. Venetucci

Research output: Contribution to journalArticlepeer-review

Abstract

Rationale: Mutations of the ryanodine receptor (RyR) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These mutations predispose to the generation of Ca waves and delayed afterdepolarizations during adrenergic stimulation. Ca waves occur when either sarcoplasmic reticulum (SR) Ca content is elevated above a threshold or the threshold is decreased. Which of these occurs in cardiac myocytes expressing CPVT mutations is unknown. Objective: We tested whether the threshold SR Ca content is different between control and CPVT and how it relates to SR Ca content during β-adrenergic stimulation. Methods and results: Ventricular myocytes from the RyR2 R4496C +/- mouse model of CPVT and wild-type (WT) controls were voltage-clamped; diastolic SR Ca content was measured and compared with the Ca wave threshold. The results showed the following. (1) In 1 mmol/L [Ca]o, β-adrenergic stimulation with isoproterenol (1μmol/L) caused Ca waves only in R4496C. (2) SR Ca content and Ca wave threshold in R4496C were lower than those in WT. (3) β-Adrenergic stimulation increased SR Ca content by a similar amount in both R4496C and WT. (4) β-Adrenergic stimulation increased the threshold for Ca waves. (5) During β-adrenergic stimulation in R4496C, but not WT, the increase of SR Ca was sufficient to reach threshold and produce Ca waves. Conclusions: In the R4496C CPVT model, the RyR is leaky, and this lowers both SR Ca content and the threshold for waves. β-Adrenergic stimulation produces Ca waves by increasing SR Ca content and not by lowering threshold.

Original languageEnglish
Pages (from-to)1483-1489
Number of pages7
JournalCirculation Research
Volume107
Issue number12
DOIs
Publication statusPublished - Dec 10 2010

Keywords

  • arrhythmia
  • ryanodine receptor
  • sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'In the RyR2R4496C mouse model of CPVT, β-adrenergic stimulation induces ca waves by increasing SR Ca content and not by decreasing the threshold for Ca Waves'. Together they form a unique fingerprint.

Cite this