SP protects cerebellar granule cells against β-amyloid-induced apoptosis by down-regulation and reduced activity of Kv4 potassium channels

• Published in: Neuropharmacology 2010, Vol.58 (1), p.268-276
• Main Authors: Pieri, M., Amadoro, G., Carunchio, I., Ciotti, M.T., Quaresima, S., Florenzano, F., Calissano, P., Possenti, R., Zona, C., Severini, C.
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - pharmacology; Animals; Animals, Newborn; Apoptosis; Aβ 23–35; Biophysics; Caspase 3 - metabolism; Cells, Cultured; Cerebellar granule cells; Cerebellum - cytology; Electric Stimulation; Ion Channel Gating - drug effects; Kv4.2 and Kv4.3 subunits; Membrane Potentials - drug effects; Membrane Potentials - physiology; Neurons - drug effects; Oncogene Protein v-akt - metabolism; Patch-Clamp Techniques - methods; Peptide Fragments - pharmacology; Phosphorylation - drug effects; Rats; Rats, Wistar; Shal Potassium Channels - drug effects; Shal Potassium Channels - metabolism; Substance P; Substance P - pharmacology; Voltage-gated K +channels
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2009.06.029

The tachykinin endecapeptide substance P (SP) has been demonstrated to exert a functional role in neurodegenerative disorders, including Alzheimer's disease (AD). Aim of the present study was to evaluate the SP neuroprotective potential against apoptosis induced by the neurotoxic beta-amyloid peptide (Aβ) in cultured rat cerebellar granule cells (CGCs). We found that SP protects CGCs against both Aβ 25–35- and Aβ 1–42-induced apoptotic CGCs death as revealed by live/dead cell assay, Hoechst staining and caspase(s)-induced PARP-1 cleavage, through an Akt-dependent mechanism. Since in CGCs the fast inactivating or A-type K + current ( I KA) was potentiated by Aβ treatment through up-regulation of Kv4 subunits, we investigated whether I KA and the related potassium channel subunits could be involved in the SP anti-apoptotic activity. Patch-clamp experiments showed that the Aβ-induced increase of I KA current amplitude was reversed by SP treatment. In addition, as revealed by Western blot analysis and immunofluorescence studies, SP prevented the up-regulation of Kv4.2 and Kv4.3 channel subunits expression. These results indicate that SP plays a role in the regulation of voltage-gated potassium channels in Aβ-mediated neuronal death and may represent a new approach in the understanding and treatment of AD.