Subcellular heterogeneity of ryanodine receptor properties in ventricular myocytes with low T-tubule density.
Subcellular heterogeneity of ryanodine receptor properties in ventricular myocytes with low T-tubule density.
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DOI：
10.1371/journal.pone.0025100
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Sipido KR
中科院分区：
文献类型：
--
作者：
Biesmans L;Macquaide N;Heinzel FR;Bito V;Smith GL;Sipido KR
在大型哺乳动物的心室肌细胞中，并非所有兰尼碱受体 (RyR) 簇都与 T 管 (TT) 相关。该比例随着心肌梗塞（MI）后细胞重塑而增加。表征基线时和 MI 后与 TT 接近度相关的 RyR 功能特性。从健康猪 (CTRL) 的左心室或心肌梗塞 (MI) 附近的区域分离出肌细胞。在共焦线扫描成像 (fluo-3) 期间，在全细胞电压钳下测量 Ca2+ 瞬变，并根据 TT 的接近程度（早期 Ca2+ 释放的位点，20 毫秒内 F>F50）或它们的缺失（延迟区域）进行分段。舒张期期间的自发 Ca2+ 释放事件、反映 RyR 活性和特性的 Ca2+ 火花随后被分配到任一类别。在 CTRL 中，TT 附近的火花频率较高，但火花持续时间明显较短。 Na+/Ca2+交换器 (NCX) 的阻断选择性地延长了 TT 附近的火花持续时间，而通过 Ca2+ 通道阻断 Ca2+ 流入并不影响火花特性。在 MI 中，总火花质量随着 SR Ca2+ 含量的增加而增加。极长的火花（>47.6 ms）更频繁地发生。近 TT 火花的比例减少；频率增加主要发生在延迟站点。仅在近 TT 火花中观察到持续时间增加； MI 中 NCX 在膜上去除的 Ca2+ 显着降低。 TT 邻近调节 RyR 簇特性，导致舒张期火花活动的细胞内异质性。 MI 附近区域的重塑对这些 RyR 亚群有不同的影响。 TT 附近火花数量的减少和局部 NCX 去除的减少限制了细胞 Ca2+ 损失并提高了 SR Ca2+ 含量，但可能促进 Ca2+ 波。
In ventricular myocytes of large mammals, not all ryanodine receptor (RyR) clusters are associated with T-tubules (TTs); this fraction increases with cellular remodeling after myocardial infarction (MI). To characterize RyR functional properties in relation to TT proximity, at baseline and after MI. Myocytes were isolated from left ventricle of healthy pigs (CTRL) or from the area adjacent to a myocardial infarction (MI). Ca2+ transients were measured under whole-cell voltage clamp during confocal linescan imaging (fluo-3) and segmented according to proximity of TTs (sites of early Ca2+ release, F>F50 within 20 ms) or their absence (delayed areas). Spontaneous Ca2+ release events during diastole, Ca2+ sparks, reflecting RyR activity and properties, were subsequently assigned to either category. In CTRL, spark frequency was higher in proximity of TTs, but spark duration was significantly shorter. Block of Na+/Ca2+ exchanger (NCX) prolonged spark duration selectively near TTs, while block of Ca2+ influx via Ca2+ channels did not affect sparks properties. In MI, total spark mass was increased in line with higher SR Ca2+ content. Extremely long sparks (>47.6 ms) occurred more frequently. The fraction of near-TT sparks was reduced; frequency increased mainly in delayed sites. Increased duration was seen in near-TT sparks only; Ca2+ removal by NCX at the membrane was significantly lower in MI. TT proximity modulates RyR cluster properties resulting in intracellular heterogeneity of diastolic spark activity. Remodeling in the area adjacent to MI differentially affects these RyR subpopulations. Reduction of the number of sparks near TTs and reduced local NCX removal limit cellular Ca2+ loss and raise SR Ca2+ content, but may promote Ca2+ waves.
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