The metabotropic P2Y 4 receptor participates in the commitment to differentiation and cell death of human neuroblastoma SH-SY5Y cells

Fabio Cavaliere, Valeria Nestola, Susanna Amadio, Nadia D'Ambrosi, Daniela F. Angelini, Giuseppe Sancesario, Giorgio Bernardi, Cinzia Volonté

Research output: Contribution to journalArticlepeer-review


Extracellular nucleotides exert a variety of biological actions through different subtypes of P2 receptors. Here we characterized in the human neuroblastoma SH-SY5Y cells the simultaneous presence of various P2 receptors, belonging to the P2X ionotropic and P2Y metabotropic families. Western blot analysis detected the P2X 1,2,4,5,6,7 and P2Y 1,2,4,6, but not the P2X 3 and P2Y 12 receptors. We then investigated which biological effects were mediated by the P2Y 4 subtype and its physiological pyrimidine agonist UTP. We found that neuronal differentiation of the SH-SY5Y cells with dibutiryl-cAMP increased the expression of the P2Y 4 protein and that UTP itself was able to positively interfere with neuritogenesis. Moreover, transient transfection and activation of P2Y 4 also facilitated neuritogenesis in SH-SY5Y cells, as detected by morphological phase contrast analysis and confocal examination of neurofilament proteins NFL. This was concurrent with increased transcription of immediate-early genes linked to differentiation such as cdk-5 and NeuroD6, and activity of AP-1 transcription family members such as c-fos, fos-B, and jun-D. Nevertheless, a prolonged activation of the P2Y 4 receptor by UTP also induced cell death, both in naive, differentiated, and P2Y 4- transfected SH-SY5Y cells, as measured by direct count of intact nuclei and cytofluorimetric analysis of damaged DNA. Taken together, our data indicate that the high expression and activation of the P2Y 4 receptor participates in the neuronal differentiation and commitment to death of SH-SY5Y cells.

Original languageEnglish
Pages (from-to)100-109
Number of pages10
JournalNeurobiology of Disease
Issue number1
Publication statusPublished - Feb 2005


  • Dibutiryl-cAMP
  • Extracellular nucleotides
  • Immediate-early genes
  • Neurofilament proteins
  • UTP

ASJC Scopus subject areas

  • Neurology

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