Departments of Pharmacology and Experimental Neuroscience, Durham Research Center, University of Nebraska Medical Center, DRC 3047, Omaha, NE, 68198-5800, USA.
Heart Fail Rev. 2014 Jan;19(1):101-12. doi: 10.1007/s10741-013-9384-9.
Efficient and rhythmic cardiac contractions depend critically on the adequate and synchronized release of Ca(2+) from the sarcoplasmic reticulum (SR) via ryanodine receptor Ca(2+) release channels (RyR2) and its reuptake via sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a). It is well established that this orchestrated process becomes compromised in diabetes. What remain incompletely defined are the molecular mechanisms responsible for the dysregulation of RyR2 and SERCA2a in diabetes. Earlier, we found elevated levels of carbonyl adducts on RyR2 and SERCA2a isolated from hearts of type 1 diabetic rats and showed the presence of these posttranslational modifications compromised their functions. We also showed that these mono- and di-carbonyl reactive carbonyl species (RCS) do not indiscriminately react with all basic amino acid residues on RyR2 and SERCA2a; some residues are more susceptible to carbonylation (modification by RCS) than others. A key unresolved question in the field is which of the many RCS that are upregulated in the heart in diabetes chemically react with RyR2 and SERCA2a? This brief review introduces readers to the field of RCS and their roles in perturbing SR Ca(2+) cycling in diabetes. It also provides new experimental evidence that not all RCS that are upregulated in the heart in diabetes chemically react with RyR2 and SERCA2a, methylglyoxal and glyoxal preferentially do.
高效且有节奏的心脏收缩依赖于肌浆网（SR）通过兰尼碱受体 Ca2+释放通道（RyR2）充分且同步地释放 Ca2+，以及通过肌浆网（endo）内质网 Ca2+-ATP 酶（SERCA2a）摄取 Ca2+。目前已经证实，这种协调的过程在糖尿病中受到了损害。但仍不完全明确的是，导致 RyR2 和 SERCA2a 在糖尿病中失调的分子机制。早些时候，我们发现 1 型糖尿病大鼠心脏中 RyR2 和 SERCA2a 的羰基加合物水平升高，并表明这些翻译后修饰使其功能受损。我们还表明，这些单羰基和二羰基反应性羰基物质（RCS）不会随机与 RyR2 和 SERCA2a 上所有碱性氨基酸残基反应；一些残基比其他残基更容易发生羰基化（RCS 修饰）。该领域的一个关键未解决的问题是，在糖尿病中，心脏中上调的许多 RCS 中哪些会与 RyR2 和 SERCA2a 发生化学反应？这篇简短的综述向读者介绍了 RCS 领域及其在糖尿病中扰乱 SR Ca2+循环的作用。它还提供了新的实验证据表明，并非所有在糖尿病中上调的 RCS 都会与 RyR2 和 SERCA2a 发生化学反应，而甲基乙二醛和乙二醛更倾向于发生这种反应。
