Up-regulation and activation of the P2Y(2) nucleotide receptor mediate neurite extension in IL-1β-treated mouse primary cortical neurons

J Neurochem. 2013 Jun;125(6):885-96. doi: 10.1111/jnc.12252. Epub 2013 Apr 25.


The pro-inflammatory cytokine interleukin-1β (IL-1β), whose levels are elevated in the brain in Alzheimer's and other neurodegenerative diseases, has been shown to have both detrimental and beneficial effects on disease progression. In this article, we demonstrate that incubation of mouse primary cortical neurons (mPCNs) with IL-1β increases the expression of the P2Y2 nucleotide receptor (P2Y2R) and that activation of the up-regulated receptor with UTP, a relatively selective agonist of the P2Y2R, increases neurite outgrowth. Consistent with the accepted role of cofilin in the regulation of neurite extension, results indicate that incubation of IL-1β-treated mPCNs with UTP increases the phosphorylation of cofilin, a response absent in PCNs isolated from P2Y2R(-/-) mice. Other findings indicate that function-blocking anti-αv β3/5 integrin antibodies prevent UTP-induced cofilin activation in IL-1β-treated mPCNs, suggesting that established P2Y2R/αv β3/5 interactions that promote G12 -dependent Rho activation lead to cofilin phosphorylation involved in neurite extension. Cofilin phosphorylation induced by UTP in IL-1β-treated mPCNs is also decreased by inhibitors of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), suggesting a role for P2Y2R-mediated and Gq-dependent calcium mobilization in neurite outgrowth. Taken together, these studies indicate that up-regulation of P2Y2Rs in mPCNs under pro-inflammatory conditions can promote cofilin-dependent neurite outgrowth, a neuroprotective response that may be a novel pharmacological target in the treatment of neurodegenerative diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actin Depolymerizing Factors / metabolism
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cerebral Cortex / cytology*
  • Integrin alphaVbeta3 / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-1beta / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurites / drug effects
  • Neurites / metabolism
  • Neurites / ultrastructure
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Phosphorylation
  • Primary Cell Culture
  • Purinergic P2Y Receptor Agonists / pharmacology
  • Receptors, Purinergic P2Y2 / genetics
  • Receptors, Purinergic P2Y2 / metabolism*
  • Receptors, Vitronectin / metabolism
  • Up-Regulation
  • Uridine Triphosphate / pharmacology


  • Actin Depolymerizing Factors
  • Integrin alphaVbeta3
  • Interleukin-1beta
  • Purinergic P2Y Receptor Agonists
  • Receptors, Purinergic P2Y2
  • Receptors, Vitronectin
  • integrin alphaVbeta5
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Uridine Triphosphate