title: Calsequestrin accumulation in rough endoplasmic reticulum promotes perinuclear Ca2+ release.
abstract: Molecular mechanisms underlying Ca(2+) regulation by perinuclear endoplasmic/sarcoplasmic reticulum (ER/SR) cisternae in cardiomyocytes remain obscure. To investigate the mechanisms of changes in cardiac calsequestrin (CSQ2) trafficking on perinuclear Ca(2+) signaling, we manipulated the subcellular distribution of CSQ2 by overexpression of CSQ2-DsRed, which specifically accumulates in the perinuclear rough ER. Adult ventricular myocytes were infected with adenoviruses expressing CSQ2-DsRed, CSQ2-WT, or empty vector. We found that perinuclear enriched CSQ2-DsRed, but not normally distributed CSQ2-WT, enhanced nuclear Ca(2+) transients more potently than cytosolic Ca(2+) transients. Overexpression of CSQ2-DsRed produced more actively propagating Ca(2+) waves from perinuclear regions than did CSQ2-WT. Activities of the SR/ER Ca(2+)-ATPase and ryanodine receptor type 2, but not inositol 1,4,5-trisphosphate receptor type 2, were required for the generation of these perinuclear initiated Ca(2+) waves. In addition, CSQ2-DsRed was more potent than CSQ2-WT in inducing cellular hypertrophy in cultured neonatal cardiomyocytes. Our data demonstrate for the first time that CSQ2 retention in the rough ER/perinuclear region promotes perinuclear Ca(2+) signaling and predisposes to ryanodine receptor type 2-mediated Ca(2+) waves from CSQ2-enriched perinuclear compartments and myocyte hypotrophy. These findings provide new insights into the mechanism of CSQ2 in Ca(2+) homeostasis, suggesting that rough ER-localized Ca(2+) stores can operate independently in raising levels of cytosolic/nucleoplasmic Ca(2+) as a source of Ca(2+) for Ca(2+)-dependent signaling in health and disease.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Ang
authors.initials: A
authors.lastname: Guo
authors.forename: Steven E
authors.initials: SE
authors.lastname: Cala
authors.forename: Long-Sheng
authors.initials: LS
authors.lastname: Song
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D018870:Endoplasmic Reticulum, Rough / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D002155:Calsequestrin; D019837:Ryanodine Receptor Calcium Release Channel; C514388:casq2 protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium