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

M. Pieri, G. Amadoro, I. Carunchio, M. T. Ciotti, S. Quaresima, F. Florenzano, P. Calissano, R. Possenti, C. Zona, C. Severini

Research output: Contribution to journalArticle

Abstract

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 Aβ25-35- and Aβ1-42-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 (IKA) was potentiated by Aβ treatment through up-regulation of Kv4 subunits, we investigated whether IKA 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 IKA 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.

Original languageEnglish
Pages (from-to)268-276
Number of pages9
JournalNeuropharmacology
Volume58
Issue number1
DOIs
Publication statusPublished - Jan 2010

Keywords

  • Apoptosis
  • Cerebellar granule cells
  • Kv4.2 and Kv4.3 subunits
  • Substance P
  • Voltage-gated Kchannels

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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    Pieri, M., Amadoro, G., Carunchio, I., Ciotti, M. T., Quaresima, S., Florenzano, F., Calissano, P., Possenti, R., Zona, C., & Severini, C. (2010). SP protects cerebellar granule cells against β-amyloid-induced apoptosis by down-regulation and reduced activity of Kv4 potassium channels. Neuropharmacology, 58(1), 268-276. https://doi.org/10.1016/j.neuropharm.2009.06.029