Department of Chemistry, University of Kentucky, 505 Rose St. Chemistry-Physics Building, Lexington, KY 40506, USA.
Department of Family & Community Nursing, University of North Carolina - Greensboro, 1008 Administration Dr. McIver Building, Greensboro, NC 27412, USA.
Cell Calcium. 2018 May;71:65-74. doi: 10.1016/j.ceca.2017.11.006. Epub 2017 Dec 8.
Hyperamylinemia is a condition that accompanies obesity and precedes type II diabetes, and it is characterized by above-normal blood levels of amylin, the pancreas-derived peptide. Human amylin oligomerizes easily and can deposit in the pancreas [1], brain [2], and heart [3], where they have been associated with calcium dysregulation. In the heart, accumulating evidence suggests that human amylin oligomers form moderately cation-selective [4,5] channels that embed in the cell sarcolemma (SL). The oligomers increase membrane conductance in a concentration-dependent manner [5], which is correlated with elevated cytosolic Ca. These findings motivate our core hypothesis that non-selective inward Ca conduction afforded by human amylin oligomers increase cytosolic and sarcoplasmic reticulum (SR) Ca load, which thereby magnifies intracellular Ca transients. Questions remain however regarding the mechanism of amylin-induced Ca dysregulation, including whether enhanced SL Ca influx is sufficient to elevate cytosolic Ca load [6], and if so, how might amplified Ca transients perturb Ca-dependent cardiac pathways. To investigate these questions, we modified a computational model of cardiomyocytes Ca signaling to reflect experimentally-measured changes in SL membrane permeation and decreased sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) function stemming from acute and transgenic human amylin peptide exposure. With this model, we confirmed the hypothesis that increasing SL permeation alone was sufficient to enhance Ca transient amplitudes. Our model indicated that amplified cytosolic transients are driven by increased Ca loading of the SR and that greater fractional release may contribute to the Ca-dependent activation of calmodulin, which could prime the activation of myocyte remodeling pathways. Importantly, elevated Ca in the SR and dyadic space collectively drive greater fractional SR Ca release for human amylin expressing rats (HIP) and acute amylin-exposed rats (+Amylin) mice, which contributes to the inotropic rise in cytosolic Ca transients. These findings suggest that increased membrane permeation induced by oligomeratization of amylin peptide in cell sarcolemma contributes to Ca dysregulation in pre-diabetes.
高胰岛淀粉样肽血症是一种伴随肥胖和 II 型糖尿病出现的病症，其特征是胰岛淀粉样肽（一种源自胰腺的肽）的血液水平高于正常水平。人类胰岛淀粉样肽容易寡聚化，并可在胰腺[1]、大脑[2]和心脏[3]中沉积，在这些部位与钙失调有关。在心脏中，越来越多的证据表明，人类胰岛淀粉样肽寡聚物形成中等阳离子选择性[4,5]通道，嵌入细胞肌膜（SL）中。寡聚物以浓度依赖的方式增加膜电导[5]，这与胞质 Ca 升高相关。这些发现促使我们提出核心假设，即人类胰岛淀粉样肽寡聚物提供的非选择性内向 Ca 传导会增加胞质和肌浆网（SR）Ca 负荷，从而放大细胞内 Ca 瞬变。然而，关于胰岛淀粉样肽诱导的 Ca 失调的机制仍存在一些问题，包括增强的 SL Ca 内流是否足以升高胞质 Ca 负荷[6]，如果是这样，放大的 Ca 瞬变如何扰乱 Ca 依赖性心脏途径。为了研究这些问题，我们修改了心肌细胞 Ca 信号的计算模型，以反映急性和转基因人类胰岛淀粉样肽暴露引起的 SL 膜通透性改变和肌浆/内质网钙 ATP 酶（SERCA）功能下降的实验测量结果。使用该模型，我们证实了这样的假设，即单独增加 SL 通透性足以增强 Ca 瞬变幅度。我们的模型表明，放大的胞质瞬变是由 SR 的 Ca 负荷增加驱动的，更大的分数释放可能有助于钙依赖性钙调蛋白的激活，这可能使肌细胞重塑途径的激活处于启动状态。重要的是，升高的 SR 和二联体空间中的 Ca 共同导致表达人类胰岛淀粉样肽的大鼠（HIP）和急性胰岛淀粉样肽暴露的大鼠（+Amylin）的 SR Ca 分数释放增加，这有助于胞质 Ca 瞬变的变力增加。这些发现表明，细胞肌膜中胰岛淀粉样肽寡聚化诱导的膜通透性增加导致糖尿病前期的 Ca 失调。
