Regulation of excitability in sinoatrial myocytes

窦房肌细胞兴奋性的调节

• 批准号: 10656412
• 负责人: CATHERINE PROENZA
• 金额: $ 51.5万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656412
• 关键词: Action Potentials; Address; Aerobic; Age; Aging; Alternative Therapies; Biophysical Process; Biophysics; Bradycardia; Cardiac; Cardiac Myocytes; Cardiac pacemaker; Cardiovascular system; Cell membrane; Cells; Cerebrum; Closure by clamp; Complement; Computer software; Custom; Cyclic AMP; Data; Dependence; Development; Diastole; Elderly; Electrophysiology (science); Funding; Gender; Goals; Guanylate kinase; HCN4 gene; Health; Health Care Costs; Heart; Heart Rate; Human; Impaired cognition; Implant; Individual; Injury; Inositol; Ion Channel; Knock-out; Life Style; Link; Mediating; Microprocessor; Molecular; Morbidity - disease rate; Mus; Muscle Cells; Neurons; Operative Surgical Procedures; Pacemakers; Phase; Phenotype; Physical Fitness; Physiological; Process; Property; Regulation; Research; Rest; Risk; Shapes; Signal Transduction; Sinoatrial Node; Societies; Syncope; System; Techniques; Testing; Time; Work; age related; aged; cost; defined contribution; dynamic system; electronic pacemaker; experimental study; functional independence; genetic regulatory protein; healthspan; improved; inorganic phosphate; insight; knock-down; mimetics; nodal myocyte; normal aging; novel; patch clamp; programs; receptor; response; tool; voltage

The long term goals of this project are to understand the molecular and biophysical mechanisms for the regulation of cardiac pacemaking in sinoatrial node myocytes (SAMs) across the gamut of physiological conditions. SAMs function as cardiac pacemaker cells by firing spontaneous action potentials (APs). As in other excitable cells, the precise shape of sinoatrial APs reflects the composite activity of the unique complement of ion channels and transporters on the plasma membrane. AP waveforms are not static; they vary in response to short- and long-term changes in physiological context. In principle, differences in AP waveforms should lend insight into the changes in ionic currents that underlie cellular electrophysiological responses. However, our ability to decode the causal relationships between ionic currents and AP shape remains an elusive goal in all excitable cells. This gap in understanding is caused by a lack of information about AP waveforms and currents in different physiological contexts and by difficulties inherent to the study of interrelated systems using conventional research approaches. The present proposal addresses these general questions by focusing on the mechanisms by which aging slows cardiac pacemaking. Proposed experiments follow from work in prior funding periods and new preliminary data which show that aging slows pacemaking in part by decreasing the spontaneous AP firing rate of SAMs in association with changes in a limited subset of AP waveform parameters and reductions in the funny current (If) and voltage-gated Ca2+ currents (ICa,L and ICa,T). They also address the prior observation that age-dependent reductions in pacemaker activity and If in SAMs can be reversed by high concentrations of exogenous cAMP via a cAMP-mimetic mechanism. Proposed experiments will use new research tools developed during the current funding period (1) to define age-dependent changes in the relative contributions of currents active during different phases of the AP in SAMs, (2) to test the ability of different currents, singly and in combination, to transform the AP phenotype of young and aged SAMs, and (3) to test the hypothesis that age-dependent reduction in a novel If regulatory protein is responsible for the hyperpolarizing shift in voltage-dependence and resulting slowing of AP firing rate in SAMs and heart rate in mice. Results of these studies will experimentally define for the first time causal links between individual ionic currents and AP waveform parameters in SAMs that are responsible for cardiac pacemaking in general and will reveal how these mechanisms are changed during normal aging.

该项目的长期目标是了解分子和生物物理机制的 在生理范围 状况。 SAMS通过发射自发作用电位（AP）充当心脏起搏器细胞。如 其他令人兴奋的细胞，辛里氏AP的精确形状反映了独特的复合活性 质膜上离子通道和转运蛋白的补体。 AP波形不是静态的；他们 随着生理环境中短期和长期变化的响应而有所不同。原则上，AP的差异 波形应深入了解基于细胞电生理基础的离子电流的变化 回答。但是，我们解码离子电流与AP形状之间的因果关系的能力 在所有激发细胞中仍然是一个难以捉摸的目标。这种理解差距是由于缺乏信息引起的 关于不同生理环境中的AP波形和电流，以及研究的困难 使用常规研究方法相互关联的系统。目前的提议解决了这些将军 通过关注衰老减慢心脏起搏的机制来进行问题。提出的实验 跟随以前的资金期间的工作和新的初步数据，这些数据表明衰老减慢了起诉 部分通过降低SAM的自发性AP触发速率以及有限子集的变化 ap波形参数和有趣电流（如果）和电压门控的Ca2+电流（ICA，L和 ICA，T）。他们还解决了先前的观察，即起搏器活动的年龄依赖性减少以及 通过营地模拟机制，高浓度的外源营地可以逆转SAM。 拟议的实验将使用当前资助期（1）中开发的新研究工具来定义 年龄依赖于AP不同阶段的电流相对贡献的年龄变化 SAMS，（2）测试不同电流的能力，单独和组合，转化AP表型 年轻和老化的SAM以及（3）测试了一个假说，即在调节的新颖中依赖年龄的降低 蛋白质负责电压依赖性的超极化转移以及AP发射速率的放缓 在小鼠的SAM和心率中。这些研究的结果将首次实验定义。 SAM中的单个离子电流与AP波形参数之间的链接，这些参数负责心脏 起搏通常会揭示在正常衰老期间这些机制如何改变。

项目成果

Regulation of HCN Channels by Protein Interactions.

• DOI: 10.3389/fphys.2022.928507
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4

Phosphorylation and modulation of hyperpolarization-activated HCN4 channels by protein kinase A in the mouse sinoatrial node.

• DOI: 10.1085/jgp.201010488
• 发表时间: 2010-09
• 期刊: The Journal of general physiology
• 作者: Liao Z;Lockhead D;Larson ED;Proenza C
• 通讯作者: Proenza C

The funny current If is essential for the fight-or-flight response in cardiac pacemaker cells.

• DOI: 10.1085/jgp.202213193
• 发表时间: 2022-12-05
• 期刊: JOURNAL OF GENERAL PHYSIOLOGY
• 影响因子: 3.8
• 作者: Peters, Colin H.;Rickert, Christian;Morotti, Stefano;Grandi, Eleonora;Aronow, Kurt A.;Beam, Kurt G.;Proenza, Catherine
• 通讯作者: Proenza, Catherine

Culture and adenoviral infection of sinoatrial node myocytes from adult mice.

• DOI: 10.1152/ajpheart.00068.2015
• 发表时间: 2015-08
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: J. S. St. Clair;Emily J. Sharpe;C. Proenza

Mammalian γ2 AMPK regulates intrinsic heart rate.

• DOI: 10.1038/s41467-017-01342-5
• 发表时间: 2017-11-02
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Yavari A;Bellahcene M;Bucchi A;Sirenko S;Pinter K;Herring N;Jung JJ;Tarasov KV;Sharpe EJ;Wolfien M;Czibik G;Steeples V;Ghaffari S;Nguyen C;Stockenhuber A;Clair JRS;Rimmbach C;Okamoto Y;Yang D;Wang M;Ziman BD;Moen JM;Riordon DR;Ramirez C;Paina M;Lee J;Zhang J;Ahmet I;Matt MG;Tarasova YS;Baban D;Sahgal N;Lockstone H;Puliyadi R;de Bono J;Siggs OM;Gomes J;Muskett H;Maguire ML;Beglov Y;Kelly M;Dos Santos PPN;Bright NJ;Woods A;Gehmlich K;Isackson H;Douglas G;Ferguson DJP;Schneider JE;Tinker A;Wolkenhauer O;Channon KM;Cornall RJ;Sternick EB;Paterson DJ;Redwood CS;Carling D;Proenza C;David R;Baruscotti M;DiFrancesco D;Lakatta EG;Watkins H;Ashrafian H
• 通讯作者: Ashrafian H