In the RyR2(R4496C) mouse model of CPVT, β-adrenergic stimulation induces Ca waves by increasing SR Ca content and not by decreasing the threshold for Ca waves.
BACKGROUND
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.


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(2+)](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.
Unit of Cardiac Physiology, Manchester Academic Health Sciences Centre, University of Manchester, 46 Grafton St, Manchester M13 9NT, United Kingdom.
Takeshi
T
Kashimura
Sarah J
SJ
Briston
Andrew W
AW
Trafford
Carlo
C
Napolitano
Silvia G
SG
Priori
David A
DA
Eisner
Luigi A
LA
Venetucci
D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D004195:Disease Models, Animal; D007545:Isoproterenol; D051379:Mice; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
D018663:Adrenergic Agents; D019837:Ryanodine Receptor Calcium Release Channel; D007545:Isoproterenol; D002118:Calcium