Novel Ca2+ wave mechanisms in cardiac myocytes revealed by multiscale Ca2+ release model.

IF 3.3 2区 医学 Q1 PHYSIOLOGY
Journal of General Physiology Pub Date : 2025-05-05 Epub Date: 2025-03-06 DOI:10.1085/jgp.202413543
Morris Vysma, James S Welsh, Derek R Laver
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引用次数: 0

Abstract

Integrating cellular sarcoplasmic reticulum (SR) Ca2+ release with the known Ca2+ activation properties of RyR2s remains challenging. The sharp increase in SR Ca2+ permeability above a threshold SR luminal [Ca2+] is not reflected in RyR2 kinetics from single-channel studies. Additionally, the current paradigm that global Ca2+ release (Ca2+ waves) arises from interacting local events (Ca2+ sparks) faces a key issue that these events rarely activate neighboring sites. We present a multiscale model that reproduces Ca2+ sparks and waves in skinned ventricular myocytes using experimentally validated RyR2 kinetics. The model spans spatial domains from 10-8 to 10-4 m and timescales from 10-6 to 10 s. Ca2+ release sites are distributed in cubic voxels (0.25-µm sides) informed by super-resolution micrographs. We use parallel computing to calculate Ca2+ transport, diffusion, and buffering. Substantial increases in SR Ca2+ release occur, and Ca2+ waves initiate when Ca2+ sparks become prolonged above a threshold SR [Ca2+]. These prolonged events (Ca2+ embers) are much more likely than Ca2+ sparks to activate release from neighboring sites and accumulate increases in cytoplasmic [Ca2+] along with an associated fall in Ca2+ buffering power. This primes the cytoplasm for Ca2+-induced Ca2+ release (CICR) that produces Ca2+ waves. Thus, Ca2+ ember formation and CICR are both essential for initiation and propagation of Ca2+ waves. Cell architecture, along with the differential effects of RyR2 opening and closing rates, collectively determines the SR [Ca2+] threshold for Ca2+ embers, waves, and the phenomenon of store overload-induced Ca2+ release.

多尺度Ca2+释放模型揭示心肌细胞中新的Ca2+波机制。
将细胞肌浆网(SR) Ca2+释放与已知的RyR2s Ca2+激活特性相结合仍然具有挑战性。在单通道研究中,srca2 +通透性的急剧增加超过阈值srluminal [Ca2+]并没有反映在RyR2动力学中。此外,目前全球Ca2+释放(Ca2+波)由相互作用的局部事件(Ca2+火花)产生的范式面临一个关键问题,即这些事件很少激活邻近的位点。我们提出了一个多尺度模型,使用实验验证的RyR2动力学在皮肤心室肌细胞中再现Ca2+火花和波。模型跨越10-8 ~ 10-4 m的空间域和10-6 ~ 10 s的时间尺度。Ca2+释放位点分布在立方体素(0.25-µm边)由超分辨率显微照片通知。我们使用并行计算来计算Ca2+的传输、扩散和缓冲。大量增加SR Ca2+释放发生,当Ca2+火花延长超过阈值SR [Ca2+]时,Ca2+波开始。这些延长的事件(Ca2+余烬)比Ca2+火花更有可能激活邻近位点的释放,并积累细胞质[Ca2+]的增加,同时伴随Ca2+缓冲能力的下降。这为Ca2+诱导的Ca2+释放(CICR)启动细胞质,产生Ca2+波。因此,Ca2+余烬的形成和CICR对于Ca2+波的起始和传播都是必不可少的。细胞结构,以及RyR2打开和关闭速率的差异影响,共同决定了Ca2+余烬,波和存储过载诱导的Ca2+释放现象的SR [Ca2+]阈值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.00
自引率
10.50%
发文量
88
审稿时长
6-12 weeks
期刊介绍: General physiology is the study of biological mechanisms through analytical investigations, which decipher the molecular and cellular mechanisms underlying biological function at all levels of organization. The mission of Journal of General Physiology (JGP) is to publish mechanistic and quantitative molecular and cellular physiology of the highest quality, to provide a best-in-class author experience, and to nurture future generations of independent researchers. The major emphasis is on physiological problems at the cellular and molecular level.
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