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(Circulation Research. 2006;99:283.)
© 2006 American Heart Association, Inc.

Cellular Biology

Sarcoplasmic Reticulum and Nuclear Envelope Are One Highly Interconnected Ca²⁺ Store Throughout Cardiac Myocyte

Xu Wu, Donald M. Bers

From the Department of Physiology, Loyola University Chicago, Maywood, Ill.

Correspondence to Donald M. Bers, Department of Physiology, Loyola University Chicago, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu

Previous ventricular myocyte studies indicated that ryanodine receptors (RyRs) are in the sarcoplasmic reticulum (SR) and are critical in excitation–contraction coupling, whereas the inositol trisphosphate (InsP₃) receptors are separately localized on the nuclear envelope (NucEn) and involved in nuclear Ca²⁺ signaling. Here, we find that both caffeine and InsP₃ receptor agonists deplete free [Ca²⁺] inside both SR and NucEn. Fluorescence recovery after photobleach (FRAP) was measured using the low-affinity Ca²⁺ indicator Fluo-5N trapped inside the SR and NucEn (where its fluorescence is high because [Ca²⁺] is &1 mmol/L). After Fluo-5N photobleach in one end of the cell, FRAP occurred, accompanied by fluorescence decline in the unbleached end with similar time constants (&2 minutes) until fluorescence regained spatial uniformity. Notably, SR and NucEn fluorescence recovered simultaneously in the bleached end. Ca²⁺ diffusion inside the SR-NucEn was also measured. SR Ca²⁺-ATPase was completely blocked but without acute SR Ca²⁺ depletion. Then caffeine was applied locally to one end of the myocyte. In the caffeine-exposed end, free SR [Ca²⁺] ([Ca²⁺]_SR) declined abruptly and recovered partially (=20 to 30 seconds). In the noncaffeine end, [Ca²⁺]_SR gradually declined with a similar , until [Ca²⁺]_SR throughout the cell equalized. We conclude that the SR and NucEn lumen are extensively interconnected throughout the myocyte. Apparent intrastore diffusion coefficients of Fluo-5N and Ca²⁺ were estimated (&8 µm² sec^–1 and 60 µm² sec^–1). This rapid luminal communication may maintain homogeneously high luminal [Ca²⁺], ensuring a robust and uniform driving force for local Ca²⁺ release events from either SR or NucEn.

Key Words: sarcoplasmic reticulum • nuclear envelope (NucEn) • fluorescence recovery after photobleach (FRAP) • caffeine

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