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Updated: May 4, 2026
Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
Published on: September 18, 2017
Sarcoplasmic reticulum Ca²⁺ release is both necessary and sufficient for SK channel activation in ventricular
Dmitry Terentyev1, Jennifer A Rochira, Radmila Terentyeva
1Cardiovascular Research Center, Division of Cardiology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island.
Insights
Small conductance calcium-activated potassium (SK) channel activation in heart cells depends on calcium release from the sarcoplasmic reticulum. This process helps reduce triggered heart activity, potentially offering an anti-arrhythmic effect in heart failure.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Ion Channel Function
Background:
- Small conductance calcium-activated potassium (SK) channels are upregulated in heart failure (HF).
- The precise activation mechanisms and functional roles of SK channels in ventricular myocytes are not well understood.
Purpose of the Study:
- To investigate if SK channel activation in ventricular myocytes requires sarcoplasmic reticulum (SR) calcium release.
- To determine if SK currents play a role in mitigating triggered cardiac activity.
Main Methods:
- Adenovirus-mediated overexpression of SK2 channels in adult rat ventricular myocytes.
- Simultaneous patch-clamp electrophysiology and confocal calcium imaging.
- Caffeine-induced SR calcium release and assessment of SK currents.
- Voltage-clamp and current-clamp recordings to analyze SK channel activation and effects on cellular electrical activity.
- Immunolocalization studies to determine SK channel distribution.
Main Results:
- SK channel activation was dependent on intracellular calcium release from the SR, sensitive to apamin.
- Depletion of SR calcium stores abolished SK currents, while SR calcium release evoked these currents.
- SK channel activation was observed during spontaneous SR calcium release events (calcium waves).
- SK channel overexpression reduced the amplitude of delayed afterdepolarizations (DADs) and shortened action potential duration.
- Overexpressed SK channels localized to sarcolemmal membranes and Z-lines.
Conclusions:
- Sarcoplasmic reticulum calcium release is both necessary and sufficient for activating SK channels in ventricular myocytes.
- SK currents contribute to action potential repolarization and attenuate DADs mediated by spontaneous calcium waves.
- Upregulation of SK channels in heart failure may exert an anti-arrhythmic effect by reducing triggered activity.
Abstract:
SK channels are upregulated in human patients and animal models of heart failure (HF). However, their activation mechanism and function in ventricular myocytes remain poorly understood. We aim to test the hypotheses that activation of SK channels in ventricular myocytes requires Ca(2+) release from sarcoplasmic reticulum (SR) and that SK currents contribute to reducing triggered activity. SK2 channels were overexpressed in adult rat ventricular myocytes using adenovirus gene transfer. Simultaneous patch clamp and confocal Ca(2+) imaging experiments in SK2-overexpressing cells demonstrated that depolarizations resulted in Ca(2+)-dependent outward currents sensitive to SK inhibitor apamin. SR Ca(2+) release induced by rapid application of 10 mM caffeine evoked repolarizing SK currents, whereas complete depletion of SR Ca(2+) content eliminated SK currents in response to depolarizations, despite intact Ca(2+) influx through L-type Ca(2+) channels. Furthermore, voltage-clamp experiments showed that SK channels can be activated by global spontaneous SR Ca(2+) release events Ca(2+) waves (SCWs). Current-clamp experiments revealed that SK overexpression reduces the amplitude of delayed afterdepolarizations (DADs) resulting from SCWs and shortens action potential duration. Immunolocalization studies showed that overexpressed SK channels are distributed both at external sarcolemmal membranes and along the Z-lines, resembling the distribution of endogenous SK channels. In summary, SR Ca(2+) release is both necessary and sufficient for the activation of SK channels in rat ventricular myocytes. SK currents contribute to repolarization during action potentials and attenuate DADs driven by SCWs. Thus SK upregulation in HF may have an anti-arrhythmic effect by reducing triggered activity.
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