Calcium Current in Human Atrial Myocytes

人心房肌细胞中的钙电流

• 批准号: 7211364
• 负责人: RONALD W JOYNER
• 金额: $ 36.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211364
• 关键词: Action Potentials; Adenosine; Adenosine A1 Receptor; Adenylate Cyclase; Adult; Age; Animals; Biopsy; Calcium; Caliber; Cardiac; Cardiac Myocytes; Cells; Coupling; Cytoplasm; Development; Electrophysiology (science); Excision; GTP-Binding Proteins; Heart Atrium; Human; Infant; Kinetics; Knowledge; Kv channel-interacting protein 2; Measures; Mediating; Molecular Biology; Muscle Cells; Neonatal; Newborn Infant; Numbers; Operative Surgical Procedures; Oryctolagus cuniculus; Patients; Pattern; Phase; Procedures; Property; Protein Phosphatase G; Recovery; Regulation; Relative (related person); Right ventricular structure; Shapes; Sodium; Techniques; Testing; Tetralogy of Fallot; Tissues; Ventricular; animal data; filamin; heart cell; man; phosphatase inhibitor; phosphoric diester hydrolase; postnatal human; receptor; repaired; response; young adult

DESCRIPTION (provided by applicant): Extrapolating pharmacological and surgical therapies from adult (AD) studies to infant (INF) patients is problematic because the knowledge of cellular electrophysiology and molecular biology of human INF heart cells is limited. We have studied developmental differences in rabbit ventricular cells and now extend these studies to atrial and ventricular cells isolated from AD, young adult (YAD) or INF patients. SA 1: Developmental differences in transient outward current of atrial cells. We will extend our studies to isolated cells and tissue from YADs (age 14-20). In addition, several other accessory beta-subunits have been found in cardiac myocytes and may interact with Kv channels and regulate the function of these channels. We will determine relative amounts of these putative regulators of human atrial Ito to determine which correlate with developmental changes in Ito kinetics.SA2: Developmental differences in amplitude and regulation of calcium current in atrial cells. We hypothesize that INF atrial cells have tonic inhibition of adenylyl cyclase (and thus of ICa) mediated by inhibitory G proteins, possibly related to constitutive activity of the adenosine A1 receptor, and that, compared to AD or YAD cells, have greater sensitivity to inhibitors of phosphatases and phosphodiesterases, and that developmental changes in basal ICa amplitude and beta-sympathetic modulation correlate with inhibitory G protein levels, receptor numbers for M2 and A1 receptors, and constitutive inhibitory activity. SA3: Modulation of atrial cell calcium transients by changes in AP waveform and developmental age. We will test the hypothesis that prolongation of the early repolarization phase of the AP increases Ca2+ entry and that YAD cells have faster removal of Ca2+ from cytoplasm than INF cells and we will determine if the Na- Ca2+ exchange current (INCX) is greater in INF vs. AD or YAD cells. SA4: Developmental differences in Ca current and transients in ventricular cells. We propose that INF cells and tissue have lower basal ICa, lower potency for ISO stimulation, higher levels of Gia3 and A1 receptors, greater inhibitory potency for adenosine, and tonic inhibition of ICa. We also propose that the YAD cells have lower levels of NCX and lower INCX, higher levels of SERCA and faster removal of Ca2+ from the cytoplasm. Previous animal studies have indicated various developmental changes in cardiac cells. We will specifically study human postnatal developmental changes in Ito regulation of ICa and intracellular Ca2+ transients.

描述（由申请人提供）：将成人（AD）研究的药物和手术治疗外推到婴儿（INF）患者是有问题的，因为人类 INF 心脏细胞的细胞电生理学和分子生物学知识有限。我们研究了兔心室细胞的发育差异，现在将这些研究扩展到从 AD、青年 (YAD) 或 INF 患者中分离的心房和心室细胞。 SA 1：心房细胞瞬时外向电流的发育差异。我们将把我们的研究扩展到 YAD（14-20 岁）的分离细胞和组织。此外，在心肌细胞中还发现了其他几种辅助β亚基，它们可能与Kv通道相互作用并调节这些通道的功能。我们将确定这些假定的人类心房 Ito 调节因子的相对量，以确定其与 Ito 动力学发育变化的相关性。SA2：心房细胞钙电流振幅和调节的发育差异。我们假设 INF 心房细胞对抑制性 G 蛋白介导的腺苷酸环化酶（以及 ICa）具有强效抑制作用，可能与腺苷 A1 受体的组成型活性有关，并且与 AD 或 YAD 细胞相比，对抑制剂具有更高的敏感性磷酸酶和磷酸二酯酶的变化，基础 ICa 振幅和 β 交感神经调节的发育变化与抑制性 G 蛋白水平、M2 受体数量相关和 A1 受体，以及组成型抑制活性。 SA3：通过 AP 波形和发育年龄的变化调节心房细胞钙瞬变。我们将测试以下假设：AP 早期复极化阶段的延长会增加 Ca2+ 的进入，并且 YAD 细胞比 INF 细胞更快地从细胞质中去除 Ca2+，并且我们将确定 INF 中的 Na-Ca2+ 交换电流 (INCX) 是否更大与 AD 或 YAD 细胞相比。 SA4：心室细胞 Ca 电流和瞬变的发育差异。我们认为INF细胞和组织具有较低的基础ICa、较低的ISO刺激效力、较高水平的Gia3和A1受体、较高的腺苷抑制效力以及ICa的强直抑制。我们还提出，YAD 细胞具有较低水平的 NCX 和较低水平的 INCX、较高水平的 SERCA 以及更快地从细胞质中去除 Ca2+。先前的动物研究表明心肌细胞发生了各种发育变化。我们将专门研究 Ito 对 ICa 和细胞内 Ca2+ 瞬变的调节的人类出生后发育变化。