title: Regulation of RYR2 by sarcoplasmic reticulum Ca(2+).
abstract: Ca(2+) is arguably the most important ion involved in the contraction of the heart. The cardiac ryanodine receptor (RyR2), the major Ca(2+) release channel located in the sarcoplasmic reticulum (SR) membrane, is responsible for releasing the bulk of Ca(2+) required for contraction. Moreover, RyR2 is also crucial for maintaining SR Ca(2+) homeostasis by releasing Ca(2+) from the SR when it becomes overloaded with Ca(2+) . During normal contraction, RyR2 is activated by cytosolic Ca(2+) , whereas during store overload conditions, the opening of RyR2 is governed by SR Ca(2+) . Although the process of the cytosolic control of RyR2 is well established, the molecular mechanism by which SR luminal Ca(2+) regulates RyR2 has only recently been elucidated and remains controversial. In addition to the activation of RyR2, SR luminal Ca(2+) also determines when the RyR2 channel closes. RyR2-mediated Ca(2+) release from the SR does not continue until the SR is completely depleted. Rather, it ceases when SR luminal Ca(2+) falls below a certain level. Given the importance of SR Ca(2+) , it is not surprising that the SR luminal Ca(2+) level is tightly controlled by SR Ca(2+) -buffering proteins. Consequently, the opening and closing of RyR2 is heavily influenced by the presence of such proteins, particularly those associated with RyR2, such as calsequestrin and the histidine-rich Ca(2+) -binding protein. These proteins appear to indirectly alter RyR2 activity by modifying the microdomain SR Ca(2+) level surrounding RyR2.
authors.affiliation: Department of Physiology and HeartOtago, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: Joe Z
authors.initials: JZ
authors.lastname: Zhang
authors.affiliation: Department of Physiology and HeartOtago, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: Helen M M
authors.initials: HM
authors.lastname: Waddell
authors.affiliation: Department of Physiology and HeartOtago, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Jones
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000473:pathology; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: Ca2+; histidine-rich Ca2+-binding protein; ryanodine receptor; sarcoplasmic reticulum; store overload