Accelerated Recovery of L-Type Ca Current Contributes to the Loss of SR Ca Release Restitution in Mice Lacking Casq2

Abstract

Cardiac Ca-release from sarcoplasmic reticulum (SR) is reduced with successively shorter coupling intervals of premature stimuli, a phenomenon known as SR Ca-release restitution. Interestingly, myocytes lacking the SR luminal Ca binding protein calsequestrin (Casq2 KO) lack SR Ca-release restitution. Here we test whether altered L-type Ca current (ICa) responsible for triggering SR Ca-release contributes to the loss of Ca-release restitution.Results: ICa was recorded in voltage-clamped ventricular myocytes isolated from Casq2 KO mice and wild-type (WT) littermates. Cells were pre-treated with ryanodine and thapsigargin to eliminate SR Ca-release. After a 1 Hz train of depolarizing stimuli (S1), ICa restitution was measured by applying premature stimuli (S2) at successively shorter S1-S2 coupling intervals. Both groups have decreased ICa at short S1-S2 intervals, but ICa recovered significantly faster in KO vs. WT myocytes (p<0.001, Figure). Eliciting Ca-release by ICa tail currents (which eliminates participation of ICa restitution) reduced the difference between WT and KO Ca-release restitutions.Conclusion: Accelerated recovery of ICa contributes to loss of SR Ca-release restitution in mice lacking Casq2 and may further increase risk for ventricular arrhythmia in vivo.View Large Image | View Hi-Res Image | Download PowerPoint Slide