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LPS-induced down-regulation of NO-sensitive guanylyl cyclase in astrocytes occurs by proteasomal degradation in nuclear bodies
BMC Pharmacology volume 7, Article number: P3 (2007)
Here we show that the decrease in sGC activity and β1 subunit protein induced by LPS (10 ng/ml, 24 h) in cultured rat cerebellar astrocytes is prevented by inhibitors of proteasome activity (MG132 5 μM; lactacystin 10 μM) whereas other protease inhibitors (calpain inhibitor 25 μM; ICE inhibitor II 100 μM and leupeptin 5 μM) were not effective. Furthermore, immunocytochemistry and confocal laser microscopy revealed that in LPS-treated cells a strong sGC β1 immunorreactivity is evident in aggregates in the cell nuclei where it co-localizes with 20S proteasomes and ubiquitin in clastosomes, nucleoplasmic substructures involved in ubiquitin-proteasome-dependent nuclear proteolysis, but do not colocalize with others proteasome-enriched structures include promyelocytic leukaemia bodies and splicing speckles. In contrast, in untreated astrocytes clastosomes are scarce and sGC β1 immunorectivity shows a diffuse cytoplasmic pattern, while in the nucleus it is very weak. A similar distribution is observed when cells are treated with LPS and the proteasome inhibitor MG132 or the protein synthesis inhibitor cycloheximide.
LPS orchestrates the recruitment of sGC-β1 protein and components of the ubiquitin-proteasome system to specialized nuclear bodies, clastosomes, suggesting a mechanism for inflammation-induced down-regulation of sGC in astrocytes.
Baltrons MA, Pedraza CE, Heneka MT, García A: β-Amyloid peptides decrease soluble guanylyl cyclase expression in astroglial cells. Neurobiol Dis. 2002, 10: 39-149. 10.1006/nbdi.2002.0492.
Pedraza CE, Baltrons MA, Heneka MT, García A: Interleukin-1β and lipopolysaccharide decrease soluble guanylyl cyclase in cells of the CNS: NO-independent destabilization of protein and NO-dependent decrease of mRNA. J Neuroimmunol. 2003, 144: 80-90. 10.1016/j.jneuroim.2003.08.034.
This work was supported by a SAF2004-01717 grant (Spain).
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Baltrons, M.A., Pifarré, P., Berciano, M.T. et al. LPS-induced down-regulation of NO-sensitive guanylyl cyclase in astrocytes occurs by proteasomal degradation in nuclear bodies. BMC Pharmacol 7, P3 (2007). https://doi.org/10.1186/1471-2210-7-S1-P3
- Guanylyl Cyclase
- Nuclear Body
- Calpain Inhibitor
- Soluble Guanylyl Cyclase
- Proteasome Inhibitor MG132