Department of Molecular Cell Biology, Laboratory of Ca(2+)-transport ATPases, K.U.Leuven, Leuven, Belgium.
Biofactors. 2009 Nov-Dec;35(6):484-99. doi: 10.1002/biof.63.
Heart failure is the leading cause of death in western countries and is often associated with impaired Ca(2+) handling in the cardiomyocyte. In fact, cardiomyocyte relaxation and contraction are tightly controlled by the activity of the cardiac sarco(endo)plasmic reticulum (ER/SR) Ca(2+) pump SERCA2a, pumping Ca(2+) from the cytosol into the lumen of the ER/SR. This review addresses three important facets that control the SERCA2 activity in the heart. First, we focus on the alternative splicing of the SERCA2 messenger, which is strictly regulated in the developing heart. This splicing controls the formation of three SERCA2 splice variants with different enzymatic properties. Second, we will discuss the role and regulation of SERCA2a activity in the normal and failing heart. The two well-studied Ca(2+) affinity modulators phospholamban and sarcolipin control the activity of SERCA2a within a narrow window. An aberrantly high or low Ca(2+) affinity is often observed in and may even trigger cardiac failure. Correcting SERCA2a activity might therefore constitute a therapeutic approach to improve the contractility of the failing heart. Finally, we address the controversies and unanswered questions of other putative regulators of the cardiac Ca(2+) pump, such as sarcalumenin, HRC, S100A1, Bcl-2, HAX-1, calreticulin, calnexin, ERp57, IRS-1, and -2.
心力衰竭是西方国家的主要致死原因，通常与心肌细胞中 Ca(2+)处理受损有关。事实上，心肌细胞的松弛和收缩受到心脏肌浆网（SR）钙泵 SERCA2a 活性的严格控制，该酶将 Ca(2+)从细胞质泵入 SR 内腔。本综述探讨了控制心脏中 SERCA2 活性的三个重要方面。首先，我们重点关注 SERCA2 信使的选择性剪接，该剪接在发育中的心脏中受到严格调控。这种剪接控制着具有不同酶特性的三种 SERCA2 剪接变体的形成。其次，我们将讨论 SERCA2a 在正常和衰竭心脏中的作用和调节。两种研究充分的 Ca(2+)亲和力调节剂肌球蛋白轻链磷酸酶和肌浆网钙转运蛋白控制着 SERCA2a 的活性，其活性范围很窄。在心力衰竭中经常观察到异常高或低的 Ca(2+)亲和力，甚至可能引发心力衰竭。因此，纠正 SERCA2a 活性可能是改善衰竭心脏收缩性的一种治疗方法。最后，我们探讨了其他假定的心脏 Ca(2+)泵调节剂的争议和未解决的问题，如肌浆网钙结合蛋白、HRC、S100A1、Bcl-2、HAX-1、钙网蛋白、钙联蛋白、ERp57、IRS-1 和 -2。
