Stabilization of Ca²⁺ signaling in cardiac muscle by stimulation of SERCA.

AIMS:In cardiac muscle, phosphorylation of the RyRs is proposed to increase their Ca²⁺ sensitivity. This mechanism could be arrhythmogenic via facilitation of spontaneous Ca²⁺ waves. Surprisingly, the level of Ca²⁺ inside the SR needed to initiate such waves has been reported to increase upon β-adrenergic stimulation, an observation which cannot be easily reconciled with elevated Ca²⁺ sensitivity of the RyRs. We tested the hypothesis that this change of Ca²⁺ wave threshold could occur indirectly, subsequent to SERCA stimulation. METHODS AND RESULTS:Cytosolic and intra-SR Ca²⁺ waves were simultaneously recorded with confocal line-scan imaging in intact and permeabilized mouse cardiomyocytes using Rhod-2 and Fluo-5-N, respectively. We analyzed changes of several Ca²⁺ signaling parameters during specific SERCA stimulation by ochratoxin A (OTA), jasmonate or the Fab fragment of a phospholamban antibody. SERCA stimulation resulted in a substantial increase of the threshold for Ca²⁺ wave initiation. Faster Ca²⁺ transient decay and SR refilling confirmed SERCA acceleration. CONCLUSIONS:These results suggest that isolated SERCA stimulation can elevate the intra-SR threshold for the generation of Ca²⁺ waves, independently of RyR phosphorylation. Simultaneously, fractional Ca²⁺ release and wave amplitudes are reduced. Thus, SERCA stimulation appears to exert a negative feed-back on the Ca²⁺-induced Ca²⁺ release mechanisms sustaining the waves. Thereby, it may be profoundly antiarrhythmic. This may be clinically relevant when therapies are applied to stimulate the SERCA activity (e.g. SERCA overexpression with gene therapy, future small molecule SERCA stimulators). Copyright © 2018 Elsevier Ltd. All rights reserved.

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