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The SphK1/S1P Axis Regulates Synaptic Vesicle Endocytosis via TRPC5 Channels
Journal of Neuroscience ( IF 5.3 ) Pub Date : 2023-05-24 , DOI: 10.1523/jneurosci.1494-22.2023
Zhong-Jiao Jiang 1 , Liang-Wei Gong 2
Affiliation  

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid concentrated in the brain, is essential for normal brain functions, such as learning and memory and feeding behaviors. Sphingosine kinase 1 (SphK1), the primary kinase responsible for S1P production in the brain, is abundant within presynaptic terminals, indicating a potential role of the SphK1/S1P axis in presynaptic physiology. Altered S1P levels have been highlighted in many neurologic diseases with endocytic malfunctions. However, it remains unknown whether the SphK1/S1P axis may regulate synaptic vesicle endocytosis in neurons. The present study evaluates potential functions of the SphK1/S1P axis in synaptic vesicle endocytosis by determining effects of a dominant negative catalytically inactive SphK1. Our data for the first time identify a critical role of the SphK1/S1P axis in endocytosis in both neuroendocrine chromaffin cells and neurons from mice of both sexes. Furthermore, our Ca2+ imaging data indicate that the SphK1/S1P axis may be important for presynaptic Ca2+ increases during prolonged stimulations by regulating the Ca2+ permeable TRPC5 channels, which per se regulate synaptic vesicle endocytosis. Collectively, our data point out a critical role of the regulation of TRPC5 by the SphK1/S1P axis in synaptic vesicle endocytosis.

SIGNIFICANCE STATEMENT Sphingosine kinase 1 (SphK1), the primary kinase responsible for brain sphingosine-1-phosphate (S1P) production, is abundant within presynaptic terminals. Altered SphK1/S1P metabolisms has been highlighted in many neurologic disorders with defective synaptic vesicle endocytosis. However, whether the SphK1/S1P axis may regulate synaptic vesicle endocytosis is unknown. Here, we identify that the SphK1/S1P axis regulates the kinetics of synaptic vesicle endocytosis in neurons, in addition to controlling fission-pore duration during single vesicle endocytosis in neuroendocrine chromaffin cells. The regulation of the SphK1/S1P axis in synaptic vesicle endocytosis is specific since it has a distinguished signaling pathway, which involves regulation of Ca2+ influx via TRPC5 channels. This discovery may provide novel mechanistic implications for the SphK1/S1P axis in brain functions under physiological and pathologic conditions.



中文翻译:

SphK1/S1P 轴通过 TRPC5 通道调节突触小泡内吞作用

1-磷酸鞘氨醇 (S1P) 是一种集中在大脑中的生物活性鞘脂,对于学习、记忆和进食行为等正常大脑功能至关重要。鞘氨醇激酶 1 (SphK1) 是大脑中负责 S1P 产生的主要激酶,在突触前末梢中含量丰富,表明 SphK1/S1P 轴在突触前生理学中的潜在作用。S1P 水平的改变在许多伴有内吞功能障碍的神经系统疾病中得到了强调。然而,SphK1/S1P轴是否可以调节神经元突触小泡内吞作用仍不清楚。本研究通过确定显性失活催化失活 SphK1 的影响来评估 SphK1/S1P 轴在突触小泡内吞作用中的潜在功能。我们的数据首次确定了 SphK1/S1P 轴在神经内分泌嗜铬细胞和两性小鼠神经元的内吞作用中的关键作用。此外,我们的Ca 2+成像数据表明,SphK1/S1P 轴可能通过调节Ca 2+ 可渗透TRPC5 通道(其本身调节突触小泡内吞作用),对长时间刺激期间突触前Ca 2+ 增加重要总的来说,我们的数据指出了 SphK1/S1P 轴对 TRPC5 的调节在突触小泡内吞作用中的关键作用。

意义声明鞘氨醇激酶 1 (SphK1) 是负责大脑 1-磷酸鞘氨醇 (S1P) 产生的主要激酶,在突触前末梢中含量丰富。SphK1/S1P 代谢的改变在许多具有突触小泡内吞作用缺陷的神经系统疾病中得到了强调。然而,SphK1/S1P轴是否可以调节突触小泡内吞作用尚不清楚。在这里,我们发现 SphK1/S1P 轴除了控制神经内分泌嗜铬细胞中单个囊泡内吞作用期间的裂变孔持续时间之外,还调节神经元中突触小泡内吞作用的动力学。突触小泡内吞作用中 SphK1/S1P 轴的调节是特异性的,因为它具有独特的信号通路,涉及通过 TRPC5 通道调节 Ca 2+流入。这一发现可能为生理和病理条件下大脑功能中的 SphK1/S1P 轴提供新的机制意义。

更新日期:2023-05-25
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