Intracellular nitric oxide mediates neuroproliferative effect of neuropeptide y on postnatal hippocampal precursor cells

J Biol Chem. 2012 Jun 8;287(24):20187-96. doi: 10.1074/jbc.M112.346783. Epub 2012 Apr 3.


Neuropeptide Y (NPY) is widely expressed in the central and peripheral nervous systems and is proliferative for a range of cells types in vitro. NPY plays a key role in regulating adult hippocampal neurogenesis in vivo under both basal and pathological conditions, although the underlying mechanisms are largely unknown. We have investigated the role of nitric oxide (NO) on the neurogenic effects of NPY. Using postnatal rat hippocampal cultures, we show that the proliferative effect of NPY on nestin(+) precursor cells is NO-dependent. As well as the involvement of neuronal nitric-oxide synthase, the proliferative effect is mediated via an NO/cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG) and extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. We show that NPY-mediated intracellular NO signaling results in an increase in neuroproliferation. By contrast, extracellular NO had an opposite, inhibitory effect on proliferation. The importance of the NO-cGMP-PKG signaling pathway in ERK1/2 activation was confirmed using Western blotting. This work unites two significant modulators of hippocampal neurogenesis within a common signaling framework and provides a mechanism for the independent extra- and intracellular regulation of postnatal neural precursors by NO.

MeSH terms

  • Animals
  • Cell Proliferation*
  • Cells, Cultured
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Intermediate Filament Proteins / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Neuropeptide Y / metabolism*
  • Neuropeptide Y / pharmacology
  • Nitric Oxide / metabolism*
  • Rats
  • Rats, Wistar


  • Intermediate Filament Proteins
  • Nerve Tissue Proteins
  • Nes protein, rat
  • Nestin
  • Neuropeptide Y
  • Nitric Oxide
  • Cyclic GMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Cyclic GMP