Role of the metabotropic P2Y 4 receptor during hypoglycemia: Cross talk with the ionotropic NMDAR1 receptor

Fabio Cavaliere, Susanna Amadio, Daniela F. Angelini, Giuseppe Sancesario, Giorgio Bernardi, Cinzia Volonté

Research output: Contribution to journalArticle


It is well established that both extracellular ATP and glutamate exert a critical role during metabolic impairment, that several P2 receptor subunits are directly involved in this action and that a strong relationship exists between glutamatergic and purinergic signals. Therefore, here we studied the molecular behavior of the purinergic metabotropic P2Y 4 and the glutamatergic ionotropic NMDAR1 receptors during hypoglycemic cell death. We find that these proteins are oppositely modulated during glucose starvation (P2Y 4 is induced, whereas NMDAR1 is inhibited) and that both P2 and NMDA antagonists can restore basal protein expression levels. Moreover, double immunofluorescence experiments with confocal laser microscopy reveal co-localization at the membrane level between the P2Y 4 and NMDAR1 receptors, in both homologous (cerebellar granule neurons) and heterologous (Hek-293) cellular systems. This is furthermore confirmed by co-immunoprecipitation experiments. Finally, when we express the P2Y 4 receptor in the heterologous SH-SY5Y neuronal cell line, hypoglycemia then causes severe cell death and simultaneous downregulation of the NMDAR1 protein. In summary, our work establishes a potential molecular interplay between P2Y 4 and NMDAR1 receptors during glucose deprivation and the causative role of the P2Y 4 during cell death.

Original languageEnglish
Pages (from-to)149-158
Number of pages10
JournalExperimental Cell Research
Issue number1
Publication statusPublished - Oct 15 2004



  • CGN
  • Co-localization
  • P2Y transfection
  • SH-SY5Y

ASJC Scopus subject areas

  • Cell Biology

Cite this