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

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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