Institute of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Biochemical and Pharmacological Center (BPC) Marburg, University of Marburg, 35032 Marburg, Germany.
Institute of Physiology and Pathophysiology, Vegetative Physiology, University of Marburg, 35037 Marburg, Germany.
Int J Mol Sci. 2023 Jun 6;24(12):9795. doi: 10.3390/ijms24129795.
encodes the pore-forming α1C subunit of the L-type Ca channel, Cav1.2. Mutations and polymorphisms of the gene are associated with neuropsychiatric and cardiac disease. Haploinsufficient rats represent a recently developed model with a behavioral phenotype, but its cardiac phenotype is unknown. Here, we unraveled the cardiac phenotype of rats with a main focus on cellular Ca handling mechanisms. Under basal conditions, isolated ventricular myocytes exhibited unaltered L-type Ca current, Ca transients (CaTs), sarcoplasmic reticulum (SR) Ca load, fractional release, and sarcomere shortenings. However, immunoblotting of left ventricular (LV) tissue revealed reduced expression of Cav1.2, increased expression of SERCA2a and NCX, and augmented phosphorylation of RyR2 (at S2808) in rats. The β-adrenergic agonist isoprenaline increased amplitude and accelerated decay of CaTs and sarcomere shortenings in both and WT myocytes. However, the isoprenaline effect on CaT amplitude and fractional shortening (but not CaT decay) was impaired in myocytes exhibiting both reduced potency and efficacy. Moreover, sarcolemmal Ca influx and fractional SR Ca release after treatment with isoprenaline were smaller in than in WT myocytes. In Langendorff-perfused hearts, the isoprenaline-induced increase in RyR2 phosphorylation at S2808 and S2814 was attenuated in compared to WT hearts. Despite unaltered CaTs and sarcomere shortenings, myocytes display remodeling of Ca handling proteins under basal conditions. Mimicking sympathetic stress with isoprenaline unmasks an impaired ability to stimulate Ca influx, SR Ca release, and CaTs caused, in part, by reduced phosphorylation reserve of RyR2 in cardiomyocytes.
编码 L 型钙通道的孔形成 α1C 亚基，Cav1.2。该基因的突变和多态性与神经精神和心脏疾病有关。单倍不足大鼠是一种最近开发的具有行为表型的模型，但它的心脏表型尚不清楚。在这里，我们揭示了 大鼠的心脏表型，主要关注细胞钙处理机制。在基础条件下，分离的心室肌细胞表现出不变的 L 型钙电流、钙瞬变（CaTs）、肌浆网（SR）Ca 负荷、分数释放和肌节缩短。然而，左心室（LV）组织的免疫印迹显示 Cav1.2 表达减少，SERCA2a 和 NCX 表达增加，RyR2（在 S2808 处）磷酸化增加。β-肾上腺素能激动剂异丙肾上腺素增加了 CaTs 和肌节缩短的幅度和衰减速度在 和 WT 肌细胞中。然而，异丙肾上腺素对 CaT 幅度和分数缩短（但不是 CaT 衰减）的作用在显示效力和效力降低的 肌细胞中受损。此外，用异丙肾上腺素处理后，肌浆膜 Ca 内流和分数 SR Ca 释放在 肌细胞中小于 WT 肌细胞。在 Langendorff 灌注心脏中，与 WT 心脏相比，异丙肾上腺素诱导的 RyR2 在 S2808 和 S2814 处磷酸化增加在 心脏中减弱。尽管 CaTs 和肌节缩短不变，但 肌细胞在基础条件下表现出钙处理蛋白的重塑。用异丙肾上腺素模拟交感神经应激会暴露出刺激 Ca 内流、SR Ca 释放和 CaTs 的能力受损，部分原因是 RyR2 的磷酸化储备减少在 心肌细胞中。
