Abstract
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.
Highlights
The natriuretic peptides are a highly conserved family of peptide hormones, primarily involved in cardiovascular function [1,2]
Previous studies have shown rat C6 glioma cells to respond to natriuretic peptides, as determined by cGMP production [59,60]
As shown (Figure 1B), C6 cells failed to respond to ANP, but C-type natriuretic peptide (CNP) caused a significant increase in cGMP accumulation
Summary
The natriuretic peptides are a highly conserved family of peptide hormones, primarily involved in cardiovascular function [1,2]. CNP binds to the clearance receptor/Npr, which was thought to act predominantly to remove circulating natriuretic peptides for intracellular degradation, but in some tissues been shown to signal through. Reduced production of CNP has been observed in patients with neurological disorders, such as Parkinson’s disease [19] and epilepsy [20] This might reflect CNP-dependent changes in blood-brain-barrier permeability, as shown in bovine brain microvascular endothelial cells and astrocytes [21]. A further function of astrocytes is that of ammonia detoxification, whereby ammonia is converted to glutamine and protects the brain from ammonia toxicity [23] This critical process is affected in humans with various neurological conditions, including ageing and Alzheimer’s disease [24], where hyperammonaemia (elevated ammonia in the blood) can be observed. GPNT cell line to establish how the natriuretic peptide system in these cell types could be affected by exposure to neurotoxins and in patients with various neurological disorders
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