Zhang Xun, Buckley Charlotte, Lee Matthew D, Chalmers Susan, Wilson Calum, McCarron John G
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
J Physiol. 2025 May;603(10):2959-2978. doi: 10.1113/JP288022. Epub 2025 May 5.
An increase in cytoplasmic Ca concentration activates multiple cellular activities, including cell division, metabolism, growth, contraction and death. In smooth muscle Ca entry via voltage-dependent Ca channels leads to a relatively uniform increase in cytoplasmic Ca levels that facilitates co-ordinated contraction throughout the cell. However certain functions triggered by voltage-dependent Ca channels require periodic, pulsatile Ca changes. The mechanism by which Ca entry through voltage-dependent channels supports both co-ordinated contraction and distinct cellular responses driven by pulsatile Ca changes is unclear. Here in intact resistance arteries we show that Ca entry via voltage-dependent Ca channels evokes Ca release via inositol triphosphate receptors (IPRs), generating repetitive Ca oscillations and waves. We also show that mitochondria play a vital role in regulating Ca signals evoked by voltage-dependent Ca entry by selectively modulating Ca release via IPRs. Depolarizing the mitochondrial membrane inhibits Ca release from internal stores, reducing the overall signal-generated Ca influx without altering the signal resulting from voltage-dependent Ca entry. Notably neither Ca entry via voltage-dependent Ca channels nor Ca release via IPRs alters mitochondrial location or mitochondrial membrane potential in intact smooth muscle cells. Collectively these results demonstrate that activation of voltage-dependent Ca channels drives Ca entry, which subsequently triggers Ca release from the internal store in smooth muscle cells. Mitochondria selectively regulate this process by modulating IPR-mediated amplification of Ca signals, ensuring that different cellular responses are precisely controlled. KEY POINTS: In smooth muscle Ca⁺ entry via voltage-dependent channels produces a uniform Ca⁺ increase, enabling co-ordinated contraction in each cell. Certain functions, however, require large, pulsatile Ca⁺ changes rather than a uniform increase. Using advanced imaging in intact arteries, we discovered that voltage-dependent Ca⁺ entry triggers internal store Ca⁺ release via IP₃ receptors, generating repetitive Ca⁺ oscillations and waves. Mitochondria selectively modulate these signals by regulating only IP₃ receptor-mediated release; neither mitochondrial location nor membrane potential is altered by either type of Ca signal. These findings demonstrate how voltage-dependent Ca⁺ entry supports both co-ordinated contraction and pulsatile Ca⁺-driven biological responses.
细胞质钙浓度的升高会激活多种细胞活动，包括细胞分裂、代谢、生长、收缩和死亡。在平滑肌中，通过电压依赖性钙通道进入细胞的钙会导致细胞质钙水平相对均匀地升高，从而促进整个细胞的协调收缩。然而，由电压依赖性钙通道触发的某些功能需要周期性的、脉动性的钙变化。通过电压依赖性通道进入细胞的钙如何既支持协调收缩又支持由脉动性钙变化驱动的不同细胞反应的机制尚不清楚。在此，我们在完整的阻力动脉中表明，通过电压依赖性钙通道进入细胞的钙会通过肌醇三磷酸受体（IPRs）引发钙释放，产生重复性的钙振荡和波。我们还表明，线粒体在调节由电压依赖性钙内流引发的钙信号中起着至关重要的作用，它通过选择性地调节IPRs介导的钙释放来实现这一点。使线粒体膜去极化会抑制从内部储存库释放钙，减少由信号产生的总体钙内流，而不会改变由电压依赖性钙内流产生的信号。值得注意的是，无论是通过电压依赖性钙通道进入细胞的钙，还是通过IPRs释放的钙，都不会改变完整平滑肌细胞中线粒体的位置或线粒体膜电位。这些结果共同表明，电压依赖性钙通道的激活驱动钙进入细胞，随后触发平滑肌细胞内部储存库释放钙。线粒体通过调节IPR介导的钙信号放大来选择性地调节这一过程，确保不同的细胞反应得到精确控制。要点：在平滑肌中，通过电压依赖性通道进入细胞的Ca⁺会使Ca⁺均匀增加，从而使每个细胞能够协调收缩。然而，某些功能需要大的、脉动性的Ca⁺变化，而不是均匀增加。通过在完整动脉中进行先进的成像，我们发现电压依赖性Ca⁺内流通过IP₃受体触发内部储存库Ca⁺释放，产生重复性的Ca⁺振荡和波。线粒体仅通过调节IP₃受体介导的释放来选择性地调节这些信号；两种类型的钙信号都不会改变线粒体的位置或膜电位。这些发现证明了电压依赖性Ca⁺内流如何既支持协调收缩又支持由脉动性Ca⁺驱动的生物学反应。
