Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 584, Issue 2, Pages 601-611Publisher
WILEY
DOI: 10.1113/jphysiol.2007.140731
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Funding
- NHLBI NIH HHS [R01 HL062231, P01 HL080101, HL62231, HL80101] Funding Source: Medline
- NIMH NIH HHS [MH53367, R29 MH053367, R01 MH053367] Funding Source: Medline
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In cardiac myocytes the type-2 inositol 1,4,5-trisphosphate receptor (IP(3)R2) 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 123 (20 mu M) and the more potent IP3R agonist adenophostin (5 mu M) 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 mu M) and adenophostin (0.5 mu M) 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 Ca 2+ 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 Ca 2+ store. The data indicate that 123 can elicit Ca 2+ release from cardiac nuclei resulting in localized nuclear Ca 2+ signals.
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