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Sensitivity of the Natriuretic Peptide/cGMP System to Hyperammonaemia in Rat C6 Glioma Cells and GPNT Brain Endothelial Cells

Regan, Jacob; Mirczuk, Samantha; Scudder, Christopher; Stacey, Emily; Khan, Sabah; Powles, Torinn; Dennis-Berron, J. Sebastian; Ginley-Hidinger, Matthew; Mcgonnell, Imelda; Volk, Holger; Strickland, Rhiannon; Tivers, Michael; Lawson, Charlotte; Lipscomb, Victoria; Fowkes, Robert


Jacob Regan

Samantha Mirczuk

Christopher Scudder

Emily Stacey

Sabah Khan

Torinn Powles

J. Sebastian Dennis-Berron

Matthew Ginley-Hidinger

Imelda Mcgonnell

Holger Volk

Rhiannon Strickland

Michael Tivers

Charlotte Lawson

Victoria Lipscomb

Robert Fowkes


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.


Regan, J., Mirczuk, S., Scudder, C., Stacey, E., Khan, S., Powles, T., …Fowkes, R. (2021). Sensitivity of the Natriuretic Peptide/cGMP System to Hyperammonaemia in Rat C6 Glioma Cells and GPNT Brain Endothelial Cells. Cells,

Journal Article Type Article
Acceptance Date Feb 11, 2021
Online Publication Date Feb 15, 2021
Publication Date Feb 15, 2021
Deposit Date Dec 26, 2020
Publicly Available Date Feb 22, 2021
Journal Cells
Publisher MDPI
Peer Reviewed Peer Reviewed
Keywords natriuretic peptides; cGMP; hyperammonaemia; astrocyte; neuroendocrinology; endothelial cells; extracellular vesicles
Public URL
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