Department of Chemistry and Biochemistry.
Mechanical and Aerospace Engineering Department, University of California, San Diego, La Jolla, CA 92093.
Mol Biol Cell. 2020 Mar 19;31(7):683-694. doi: 10.1091/mbc.E19-09-0536. Epub 2019 Dec 11.
The formation and disruption of synaptic connections during development are a fundamental step in neural circuit formation. Subneuronal structures such as neurites are known to be sensitive to the level of spontaneous neuronal activity, but the specifics of how neurotransmitter-induced calcium activity regulates neurite homeostasis are not yet fully understood. In response to stimulation by neurotransmitters such as acetylcholine, calcium responses in cells are mediated by the Gαq/phospholipase Cβ (PLCβ)/phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) signaling pathway. Here, we show that prolonged Gαq stimulation results in the retraction of neurites in PC12 cells and the rupture of neuronal synapses by modulating membrane tension. To understand the underlying cause, we dissected the behavior of individual components of the Gαq/PLCβ/PI(4,5)P pathway during retraction and correlated these with the retraction of the membrane and cytoskeletal elements impacted by calcium signaling. We developed a mathematical model that combines biochemical signaling with membrane tension and cytoskeletal mechanics to show how signaling events are coupled to retraction velocity, membrane tension, and actin dynamics. The coupling between calcium and neurite retraction is shown to be operative in the nervous system. This study uncovers a novel mechanochemical connection between Gαq/PLCβ /PI(4,5)P that couples calcium responses with neural plasticity.
在发育过程中，突触连接的形成和破坏是神经回路形成的基本步骤。已知亚神经元结构（如神经突）对自发性神经元活动水平敏感，但神经递质诱导的钙活性如何调节神经突动态平衡的具体细节尚不完全清楚。在受到神经递质（如乙酰胆碱）刺激时，细胞内的钙反应由 Gαq/磷脂酶 Cβ (PLCβ)/磷脂酰肌醇 4,5-二磷酸 (PI(4,5)P)信号通路介导。在这里，我们表明，通过调节膜张力，长时间的 Gαq 刺激会导致 PC12 细胞中的神经突回缩和神经元突触破裂。为了了解其潜在原因，我们在回缩过程中对 Gαq/PLCβ/PI(4,5)P 途径的各个组成部分的行为进行了剖析，并将这些行为与受钙信号影响的膜和细胞骨架元件的回缩相关联。我们开发了一个数学模型，该模型将生化信号与膜张力和细胞骨架力学结合起来，以显示信号事件如何与回缩速度、膜张力和肌动蛋白动力学相关联。钙和神经突回缩之间的耦合在神经系统中是可行的。这项研究揭示了 Gαq/PLCβ/PI(4,5)P 之间的一种新的机械化学连接，它将钙反应与神经可塑性联系起来。
