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¹ Department of Physiology, Loyola University Chicago, Maywood, IL 60153, USA

In cardiac myocytes the type-2 inositol 1,4,5-trisphosphate receptor (IP₃R2) is the predominant isoform expressed. The IP₃R2 channel is localized to the SR and to the nuclear envelope. We studied IP₃-dependent nuclear Ca²⁺ signals ([Ca²⁺]_Nuc) in permeabilized atrial myocytes and in isolated cardiac nuclei. In permeabilized myocytes IP₃ (20 µM) and the more potent IP₃R agonist adenophostin (5 µM) caused an elevation of [Ca²⁺]_Nuc. An IP₃-dependent increase of [Ca²⁺]_Nuc was still observed after pretreatment with tetracaine to block Ca²⁺ release from ryanodine receptors (RyRs), and the effect of IP₃ was partially reversed or prevented by the IP₃R blockers heparin and 2-APB. Isolated nuclei were superfused with an internal solution containing the Ca²⁺ indicator fluo-4 dextran. Exposure to IP₃ (10 µM) and adenophostin (0.5 µM) increased [Ca²⁺]_Nuc by 25 and 27%, respectively. [Ca²⁺]_Nuc increased to higher levels than [Ca²⁺]_Cyt immediately adjacent to the outer membrane of the nuclear envelope, suggesting that a significant portion of nuclear IP₃ receptors are facing the nucleoplasm. When nuclei were pretreated with heparin or 2-APB, IP₃ failed to increase [Ca²⁺]_Nuc. Isolated nuclei were also loaded with the membrane-permeant low-affinity Ca²⁺ probe fluo-5N AM which compartmentalized into the nuclear envelope. Exposure to IP₃ and adenophostin resulted in a decrease of the fluo-5N signal that could be prevented by heparin. Stimulation of IP₃R caused depletion of the nuclear Ca²⁺ stores by approximately 60% relative to the maximum depletion produced by the ionophores ionomycin and A23187. The fluo-5N fluorescence decrease was particularly pronounced in the nuclear periphery, suggesting that the nuclear envelope may represent the predominant nuclear Ca²⁺ store. The data indicate that IP₃ can elicit Ca²⁺ release from cardiac nuclei resulting in localized nuclear Ca²⁺ signals.

(Received 13 July 2007; accepted after revision 29 August 2007; first published online 30 August 2007)
Corresponding author L. A. Blatter: Department of Physiology, Loyola University Chicago, 2160 S. First Ave., Maywood, IL 60153, USA. Email: lblatte{at}lumc.edu

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