Endocrine Signalling Group, Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK.
Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, UK.
Cells. 2021 Feb 15;10(2):398. doi: 10.3390/cells10020398.
C-type natriuretic peptide (CNP) is the major natriuretic peptide of the central nervous system and acts via its selective guanylyl cyclase-B (GC-B) receptor to regulate cGMP production in neurons, astrocytes and endothelial cells. CNP is implicated in the regulation of neurogenesis, axonal bifurcation, as well as learning and memory. Several neurological disorders result in toxic concentrations of ammonia (hyperammonaemia), which can adversely affect astrocyte function. However, the relationship between CNP and hyperammonaemia is poorly understood. Here, we examine the molecular and pharmacological control of CNP in rat C6 glioma cells and rat GPNT brain endothelial cells, under conditions of hyperammonaemia. Concentration-dependent inhibition of C6 glioma cell proliferation by hyperammonaemia was unaffected by CNP co-treatment. Furthermore, hyperammonaemia pre-treatment (for 1 h and 24 h) caused a significant inhibition in subsequent CNP-stimulated cGMP accumulation in both C6 and GPNT cells, whereas nitric-oxide-dependent cGMP accumulation was not affected. CNP-stimulated cGMP efflux from C6 glioma cells was significantly reduced under conditions of hyperammonaemia, potentially via a mechanism involving changed in phosphodiesterase expression. Hyperammonaemia-stimulated ROS production was unaffected by CNP but enhanced by a nitric oxide donor in C6 cells. Extracellular vesicle production from C6 cells was enhanced by hyperammonaemia, and these vesicles caused impaired CNP-stimulated cGMP signalling in GPNT cells. Collectively, these data demonstrate functional interaction between CNP signalling and hyperammonaemia in C6 glioma and GPNT cells, but the exact mechanisms remain to be established.
C 型利钠肽（CNP）是中枢神经系统的主要利钠肽，通过其选择性鸟苷酸环化酶-B（GC-B）受体发挥作用，调节神经元、星形胶质细胞和内皮细胞中环鸟苷酸（cGMP）的产生。CNP 参与神经发生、轴突分叉以及学习和记忆的调节。几种神经紊乱导致氨（高氨血症）的毒性浓度增加，这会对星形胶质细胞功能产生不利影响。然而，CNP 与高氨血症之间的关系尚未得到充分理解。在这里，我们研究了 CNP 在大鼠 C6 神经胶质瘤细胞和大鼠 GPNT 脑内皮细胞中的分子和药理学控制，在高氨血症条件下。高氨血症浓度依赖性抑制 C6 神经胶质瘤细胞增殖不受 CNP 共同处理的影响。此外，高氨血症预处理（1 小时和 24 小时）导致 C6 和 GPNT 细胞中随后的 CNP 刺激的 cGMP 积累显著抑制，而一氧化氮依赖性 cGMP 积累不受影响。在高氨血症条件下，CNP 刺激的 C6 神经胶质瘤细胞 cGMP 外排显著减少，潜在机制可能涉及磷酸二酯酶表达的改变。高氨血症刺激的 ROS 产生不受 CNP 影响，但在 C6 细胞中被一氧化氮供体增强。C6 细胞中细胞外囊泡的产生增加，这些囊泡导致 GPNT 细胞中 CNP 刺激的 cGMP 信号受损。总之，这些数据表明 CNP 信号与 C6 神经胶质瘤和 GPNT 细胞中的高氨血症之间存在功能相互作用，但确切的机制仍有待确定。
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